Interaction Between the Complement System and Infectious Agents – A Potential Mechanistic Link to Neurodegeneration and Dementia

Abstract

As part of the innate immune system, complement plays a critical role in the elimination of pathogens and mobilization of cellular immune responses. In the central nervous system (CNS), many complement proteins are locally produced and regulate nervous system development and physiological processes such as neural plasticity. However, aberrant complement activation has been implicated in neurodegeneration, including Alzheimer’s disease. There is a growing list of pathogens that have been shown to interact with the complement system in the brain but the short- and long-term consequences of infection-induced complement activation for neuronal functioning are largely elusive. Available evidence suggests that the infection-induced complement activation could be protective or harmful, depending on the context. Here we summarize how various infectious agents, including bacteria (e.g., Streptococcus spp.), viruses (e.g., HIV and measles virus), fungi (e.g., Candida spp.), parasites (e.g., Toxoplasma gondii and Plasmodium spp.), and prion proteins activate and manipulate the complement system in the CNS. We also discuss the potential mechanisms by which the interaction between the infectious agents and the complement system can play a role in neurodegeneration and dementia.

Introduction

The Complement System

The complement system is an evolutionarily conserved proteolytic cascade, consisting of over 40 components (Schartz and Tenner, 2020). Complement plays a key role as part of the innate immunity, eliminating pathogens and damaged cells, directly killing bacteria by forming the so-called membrane attack complex (MAC), and promoting inflammatory responses via the generation of anaphylatoxins (Yanamadala and Friedlander, 2010). The activation of the complement system can be triggered via three pathways: the classical pathway, the lectin pathway, and the alternative pathway (Veerhuis et al., 2011; Figure 1).

FIGURE 1

Each of the activation pathways leads to the formation of C3 convertase (C4bC2b or C3bBb) that cleaves the third complement component (C3) into the C3a and C3b fragments, the latter of which functions as an opsonin, forms the C3 convertase of the alternative pathway (C3bBb) and takes part in the next step of the activation cascade, i.e., proteolytic cleavage of C5. C5 activation results in the release of C5a and the formation of MAC, a.k.a. the terminal complement complex, C5b-9. C3a and C5a are peptides with anaphylatoxin properties and function as fluid-phase inflammatory mediators. They exert their biological effects mainly through the cognate membrane-bound receptors C3a receptor (C3aR) and C5a receptor (C5aR1), respectively. C5a can also bind to the second C5a-like receptor (C5L2, C5aR2). C5aR1 can propagate proinflammatory signals to induce cytokine/chemokine release and mediate the chemoattraction and activation of neutrophils and macrophages (Mathern and Heeger, 2015). C3aR signaling is immunomodulatory, exerting pro- or anti-inflammatory effects in a context-dependent manner (Coulthard and Woodruff, 2015). For example, C3aR activation enhances phagocytosis by macrophages (Wu et al., 2019) and suppresses injury-induced mobilization of neutrophils (Wu et al., 2013; Brennan et al., 2019). Besides its C3aR-mediated actions, C3a has a direct anti-microbial activity (Pasupuleti et al., 2007), indicating its multiple modes of action as an anti-infective agent. Even without antibodies, complement can neutralize pathogens (Speth et al., 2002). In addition, there are links between complement and adaptive immunity, such as the robust augmentation of antibody responses mediated by the C3d fragment (proteolytically generated from C3b) and complement receptor 2 (CR2) (Dempsey et al., 1996) and the regulation of T cell activation by C3a/C5a (Lalli et al., 2008). Thus, the complement system has crucial functions in both innate and adaptive immune responses (Mathern and Heeger, 2015). In addition, recent reports show that a number of cell types store intracellular C3 (Elvington et al., 2016), which has been proposed to have an important role in the regulation of cellular homeostasis (Liszewski et al., 2017). For example, cathepsin L-mediated intracellular C3 cleavage and C3a generation are required for homeostatic T cell survival (Liszewski et al., 2013). Airway epithelial cells can de novo synthesize C3, and intracellular C3 protects these cells from stress-induced cell death (Kulkarni et al., 2019). Intracellular C3 is also required for autophagic turnover of pancreatic β cells during diabetic stress (King et al., 2019). Notably, C3 is an evolutionarily ancient protein; it is considered to be the first element of the original complement system, whose primary role was to guard intracellular environment and homeostasis from various stimuli (Elvington et al., 2016). While complement is widely acknowledged as part of vertebrate humoral immunity, the significance of intracellular complement is less recognized. The potential role for intracellular C3 in self-defense against infection warrants further investigation.

The classical pathway is initiated by binding of C1 (C1qrs) to activators such as immune complexes, microbes, apoptotic cells, and some specific proteins including fibrillar amyloid β (Aβ) (Veerhuis et al., 2011). The lectin pathway is activated by binding of mannose-binding lectin (MBL) and ficolin to carbohydrates on microorganisms or dying cells (Veerhuis et al., 2011). The classical and lectin pathways converge at the proteolytic cleavage of C4 and C2 and the formation of C4bC2b, the C3 convertase shared by these pathways. The alternative pathway continuously generates low levels of C3-derived activation products and C3 convertase C3bBb, providing a natural immunity to microbes (Farriesa and Atkinson, 1991). The activation of alternative pathway can also occur as a result of direct interaction between C3b and pathogenic molecules, including fibrillar Aβ, further amplifying the downstream of complement cascade (Tenner, 2020). C3 and C5 can be cleaved also by MASP 1 (Matsushita and Fujita, 1995), neutrophil elastase (Yuan et al., 2015), cathepsins (Liszewski et al., 2013; Yuan et al., 2015), granulocyte proteases (Johnson et al., 1976), lysosomal enzymes, kallikrein, coagulation factors XIa, Xa, IXa, thrombin, and plasmin (Markiewski and Lambris, 2007; Amara et al., 2010). This non-convertase mode of activation is also called the extrinsic pathway.

Under physiological conditions, complement activity is tightly regulated by regulators of complement activation (RCA) to safeguard against autologous tissue injury. The RCAs that limit complement activation both in time and space include factor H (FH), factor I, C1-inhibitor, C4-binding protein, clusterin, vitronectin, CD46 (membrane cofactor protein, MCP), CD55 (decay accelerating factor, DAF), and complement receptor 1 (CR1, CD35). Properdin (FP), on the other hand, acts as a positive regulator that stabilizes the alternative pathway C3-convertase (Figure 1).

The Complement System in the CNS

Although the liver is the major source of circulating soluble complement proteins (Perlmutter and Colten, 1986), it is now established that complement components are locally synthesized throughout the body, including the brain (Woodruff et al., 2010; Tenner et al., 2018). Complement proteins, including the regulatory factors and receptors, are produced by glia and neurons (Gasque et al., 1998; Ischenko et al., 1998; Nataf et al., 1999), and recent studies have revealed a range of non-immune functions of the complement system in the CNS. For example, complement deposition on synapses, followed by CR3-dependent microglial engulfment and elimination of C1q- and C3b/iC3b-tagged synapses, plays a crucial role in synaptic pruning during normal development (Schafer et al., 2012). C3aR and C5aR are expressed by neurons and glia in the brain under normal and pathological conditions (Barnum et al., 2002). C3aR signaling regulates neuronal migration during CNS development (Gorelik et al., 2017), controls neural progenitor cell proliferation (Coulthard et al., 2018), differentiation and migration in vitro (Shinjyo et al., 2009), and promotes basal as well as injury-induced neurogenesis in the adult mouse brain (Rahpeymai et al., 2006; Shinjyo et al., 2009; Stokowska and Pekna, 2018). Notably, mice lacking C3 exhibit excessive number of synapses as young adults (Stevens et al., 2007; Perez-Alcazar et al., 2014) and neuronal migration defects characteristic of autism spectrum disorder (Gorelik et al., 2017), and are protected against age-related loss of synapses in the hippocampus (Shi et al., 2015). Higher expression of C4 in the brain has been implicated in excessive loss of synapses and development of schizophrenia (Sekar et al., 2016). C3aR deficiency is associated with altered morphology of the hippocampus and amygdala, mild cognitive impairment and hyperactive behavior in unchallenged mice (Coulthard et al., 2018; Pozo-Rodrigálvarez et al., 2021) as well as reduced neural plasticity responses after ischemic brain injury (Stokowska et al., 2017). Thus, the complement system is required for the normal development and function of the CNS.

Considering the broad range of neurodevelopmental and neuroregulatory functions of complement in the brain, it is not surprising that dysfunction or aberrant activation of the complement system have been implicated in the pathogenesis of a number of brain disorders (Gasque et al., 2000; Morgan, 2015). More specifically, complement activation has been observed in human neurodegenerative diseases, such as Alzheimer’s disease (AD), prion disease, chromosome 13 dementias (Eikelenboom et al., 2002; Rostagno et al., 2002; Morgan, 2018), as well as other neurological disorders associated with the blood-brain barrier (BBB) dysfunctions such as cerebrovascular disease, multiple sclerosis (MS) (Storch et al., 1998), and meningitis (Koelman et al., 2019). In infection, while providing protection against pathogens, excessive or prolonged activation of the complement system can lead to exaggerated inflammation and unfavorable outcomes (Ross and Densen, 1984; Figure 1).

Complement and Dementia

Dementia is a broad term for conditions with progressive memory impairment, executive and behavioral anomaly, and emotional problems, affecting the ability to perform day-to-day activities. Complement activation is implicated in AD, the most prevalent form of dementia (Rubio-Perez and Morillas-Ruiz, 2012). Together with glial activation and pro-inflammatory cytokine release, complement activation occurs during the early stage of the disease progression (Aiyaz et al., 2012). As described above, amyloid proteins stimulate complement activity (Veerhuis et al., 2011; Tenner, 2020), leading to the activation of the surrounding glial cells and local chronic inflammation (Cadman and Puttfarcken, 1997; Veerhuis et al., 2011). Complement proteins are present in amyloid plaques in the brain (Aiyaz et al., 2012), and co-localize with Aβ in the brain capillaries of cerebral amyloid angiopathy (Matsuo et al., 2017), suggesting that complement activation is a key event associated with amyloid deposition. In addition, complement is likely involved in other forms of dementia, including chromosome 13 dementias (familial British dementia FBD and familial Danish dementia FDD). Similar to AD, chromosome 13 dementias are associated with neurodegeneration and amyloid deposition in the CNS. In spite of the structural differences in the disease-associated amyloid proteins (Aβ in AD, ABri in FBD, ADan in FDD), neurodegeneration and amyloid deposition, associated with glial activation and local inflammation, are the common hallmark in all of these dementias (Saul et al., 2013). Importantly, complement activation products co-localize with amyloid plaques and related deposits in FBD and FDD (Rostagno et al., 2002). ABri and ADan synthetic peptides activate classical and alternative complement pathways, leading to the formation of the terminal complex (C5b-9). These data suggest that chronic complement activation associated with amyloid deposits may be a contributing factor to dementia progression in chromosome 13 dementias as well as in AD. While experimental evidence points to the critical function of complement in Aβ clearance (Wyss-Coray et al., 2002), and C3- and CR3-dependent microglial phagocytosis appears to play a beneficial role in the elimination of foreign pathogens as well as Aβ (Fu et al., 2012), CR3 also limits Aβ clearance from the brain interstitial fluid (Czirr et al., 2017), and is involved in Aβ-induced microglia-mediated loss of synapses in AD (Hong et al., 2016). The complexity of the involvement of complement in AD type of neurodegeneration is further highlighted by findings in the C3 deficient mice carrying the AD-associated mutations in the amyloid polypeptide and presenilin 1 genes. In this model, the C3 deficiency was protective against plaque-related synapse and neuron loss as well as cognitive decline, despite higher plaque burden (Shi et al., 2017). In addition, C1q and CR3 are required for the clearance of neuronal debris by microglia, at least in the context of injury-induced neurodegeneration (Norris et al., 2018). By virtue of its proinflammatory functions, C5a plays a significant role in neurodegeneration, including AD (Landlinger et al., 2015). Jointly, these reports point to the role of the complement system in Aβ and debris clearance as well as synapse elimination, Aβ-induced neurodegeneration and dementia.

Complement and Brain Infection

In the presence of an intact BBB, circulating immune cells, such as B- and T-lymphocytes, have limited access to the CNS. As a result, the defense of brain tissue against invading pathogens is largely dependent on local innate immunity, in particular the complement system. A number of pathogens escape the peripheral immune responses and enter the CNS. The interaction between pathogens and complement can lead to the clearance of pathogens, however, it may also contribute to tissue damage. Here we summarize the interactions between complement and infectious organisms, including bacteria, viruses, fungi, and parasites (Table 1), and discuss the potential impact of these interactions on CNS function. The interactions between complement and prion proteins are also discussed.

Interactions Between Infectious Agents and Complement in the CNS

Bacteria

Genetic defects in the complement system increase the susceptibility to bacterial infection (Brouwer et al., 2009). C2, factor D (FD), and FP deficiencies are associated with predisposition to meningococcal disease (Fijen et al., 1999; Jönsson et al., 2005; Sprong et al., 2006), while single-nucleotide polymorphisms (SNPs) in MBL are associated with pneumococcal disease (Brouwer et al., 2009). FH genotype 496C/C is associated with meningococcal disease (Haralambous et al., 2006) as is a locus in the FH (CFH) region (Davila et al., 2010). C3a exhibits anti-microbial activity against Gram-negative and Gram-positive bacteria (Pasupuleti et al., 2007). These data show that complement-dependent immune response is crucial in the protection against bacterial infection.

The evidence for the involvement of the complement system in bacterial meningitis is summarized in Table 1.1. Bacterial meningitis is an acute inflammation caused by infection in the meninges that envelope and protect the brain and spinal cord. Commonly caused by Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes, bacterial meningitis is a major health threat, the morbidity and mortality of which are driven by dysregulated host immune reactions (Mook-Kanamori et al., 2011; van de Beek et al., 2016).

As the long-term sequelae of bacterial meningitis include cognitive impairment, infection-induced inflammation may have lasting or even permanent impact on brain function (van de Beek et al., 2004), and there is strong experimental and clinical evidence for the detrimental role of complement in meningitis. Inhibition of the classical pathway and of C5 were both protective against meningitis caused by S. pneumoniae in rodents (Zwijnenburg et al., 2007; Woehrl et al., 2011), and a single nucleotide polymorphism of C5 (rs17611, encoding V802I) was associated with poor outcome in pneumococcal meningitis patients (Woehrl et al., 2011), indicating that the activation of the classical complement pathway plays a key role in the pathogenesis. In murine bacterial meningitis model, L. monocytogenes infection caused the up-regulation of C3 and FB mRNA levels in the cerebrospinal fluid (CSF) as well as in parenchymal neurons (Stahel et al., 1997), implicating local activation of the alternative pathway in the brain during meningitis. C3aR is up-regulated in glial cells and infiltrating immune cell populations in the brain tissue autopsy from bacterial meningitis patients (Gasque et al., 1998), and C5aR deficient mice were less susceptible to meningitis development despite unaltered bacterial titers in the brain (Woehrl et al., 2011), suggesting the important roles for anaphylatoxin receptor signaling in infection-induced neuroinflammation.

FH and CD46, the negative regulators of the complement system, contribute to or even enable of bacterial dissemination into the CNS. FH binding protein (Fhb) is a meningococcal protein that binds to human FH. The interaction between Fhb and host FH enables the bacteria to evade the innate immune attack, thereby facilitating systemic dissemination. Streptococcus suis, a zoonotic bacterium causing bacterial meningitis (Dominguez-Punaro et al., 2007), expresses Fhb, which contributes to the S. suis virulence via inhibition of C3b/iC3b deposition on the bacterial surface (Pian et al., 2012). In addition, Fhb can contribute to the development of severe meningitis by enhancing the traversal of S. suis across the BBB, as suggested by in vivo and in vitro experiments (Kong et al., 2017). Similarly, CD46 acts as the entry receptor for a number of microbes, including N. meningitidis, an exclusively human pathogen. While CD46 is ubiquitously expressed in human tissues, it is only expressed in the eye and spermatozoa in mouse (Liszewski et al., 2000; Lyzogubov et al., 2014). N. meningitidis does not enter the brain in wild-type mice. However, in genetically engineered mice that express human CD46 (human CD46 transgenic), N. meningitidis traversed BBB, leading to significantly higher mortality (Johansson et al., 2003). In addition to delayed bacterial clearance from the circulation, microglial and astroglial activation was observed in the brain of CD46 transgenic mice (Johansson et al., 2005). These data suggest that N. meningitidis utilizes CD46 to facilitate its own entry into the CNS.

Systemic infection and sepsis can sensitize the brain to inflammation via complement activation, even without the bacteria entering the CNS. In preterm infants, S. epidermidis triggers cerebral inflammation, white matter injury and impaired neurodevelopment (Bi et al., 2015). While Toll-like receptor 2 (TLR2) is thought to be the major contributor to neonatal infection caused by Gram-positive bacteria, the observation that the CSF levels of C1r, C3, and C5 were rapidly increased in S. epidermidis infection-induced sepsis model in pigs (Muk et al., 2019) suggests that systemic infection may cause CNS injury via aberrant activation of the complement cascade. Bacterial lipopolysaccharide-induced long-term depression via microglial CR3 activation offers a specific mechanistic link between neuroinflammation, complement activation, synaptic dysfunction, and memory impairments (Zhang et al., 2014).

While complement protects the host against bacterial infection, excessive complement activation can contribute to CNS injury and long lasting or permanent dysfunction. In addition, several complement components and regulators are exploited by bacteria to facilitate their entry into the CNS.

Viruses

A large number of brain disease-causing viruses, including herpes viruses (human herpes virus 1 [HSV-1], human herpesvirus 6 [HHV-6], and γ-herpesviruses), HIV, measles virus, Borna disease virus (BDV), Theiler’s murine encephalitis virus (TMEV), Venezuelan equine encephalitis virus (VEEV), West Nile virus (WNV), and Zika virus (ZIKV), interact with the complement system in the CNS (Table 1.2) and this interaction may play a role in neurodegeneration. Latent HSV-1 infection is associated with increased risk for AD (Itzhaki, 2018). HHV-6A and HHV-6B are frequently found in patients with neuroinflammatory diseases including MS (Alvarez-Lafuente et al., 2006) and AD (Readhead et al., 2018). γ-herpesviruses, including human Epstein–Barr virus (EBV or HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV or HHV-8), also establish life-long latency in the host, which is associated with increased risk of diverse neurological conditions, including meningitis, encephalitis, HIV-related CNS lymphoma, and MS (Said et al., 1997; Bossolasco et al., 2006; Serafini et al., 2007). Seropositivity for EBV is associated with clinical AD (Carbone et al., 2014). In HIV patients, KSHV infection can manifest in the CNS (Andrews et al., 2011; Baldini et al., 2013; Tso et al., 2017). In addition, HIV can cause cognitive impairment, so called HIV-associated neurocognitive disorders (HAND, NeuroAIDS). Indeed, while antiretroviral therapy effectively inhibits viral replication and reduces mortality, more than 50% of HIV-positive individuals suffer from cognitive impairment (Clifford, 2017; Olivier et al., 2018). Even though antiretroviral therapy suppresses viral replication, neurotoxic HIV proteins, such as Tat, continue to be produced in the CNS, leading to persistent inflammation (Liu et al., 2014; Avalos et al., 2017). WNV is a neuroinvasive pathogen that causes significant neuronal loss, inflammation, and microglial activation (Clarke et al., 2014). WNV targets hippocampal neurons (Armah et al., 2007), and patients recovering from WNV disease often suffer from cognitive impairment (Sejvar et al., 2003; Sadek et al., 2010). ZIKV is the causative agent of Zika fever, congenital infection which leads to severe developmental neurodevelopmental defects, including neonatal microcephaly (Rasmussen et al., 2016; Russo et al., 2017). The fact that ZIKV infection in adults can lead to neurological complications such as acute myelitis, encephalomyelitis, encephalitis, meningoencephalitis, and sensory polyneuropathy (Mécharles et al., 2016; Brito Ferreira et al., 2017), further strengthens the notion that ZIKV is highly neurotropic (Souza et al., 2019). VEEV is endemic to Central and South America and periodically emerges from the enzootic cycle to cause infection in human and equid populations (Weaver and Barrett, 2004), occasionally causing severe encephalomyelitis (Weaver et al., 2004). Measles virus infects over 40 million individuals per year (McChesney and Oldstone, 1989). Acute infection can cause encephalomyelitis, the neurological sequelae of which include subacute sclerosing panencephalitis (SSPE) and measles inclusion body encephalitis (MIBE) (Griffin, 2020).

The complement system provides the first line of defense against viruses, including HSV-1 via the lectin pathway (Bibert et al., 2019), and γ-herpesvirus, VEEV, and WNV via C3-dependent elimination mechanisms (Kapadia et al., 2002; Mehlhop et al., 2005; Brooke et al., 2012). On the other hand, the virus-induced up-regulation of complement components in the CNS may lead to BBB dysfunction and contribute to tissue damage in infection with HIV and TMEV (Speth et al., 2004; Woollard et al., 2014; Libbey et al., 2017). For example, HIV-Tat protein upregulated C3 expression in human brain microvascular endothelial cells (HBMEC) in vitro (Woollard et al., 2014), C1q is up-regulated in the brain of Simian immunodeficiency virus (SIV)-infected rhesus macaques (Speth et al., 2004; Depboylu et al., 2005) and mice after HIV-Tat injection into the cerebral cortex (Hammond et al., 2018), two in vivo models of NeuroAIDS. Increased C1q in the CSF is associated with cognitive impairment in HIV-infected individuals (McGuire et al., 2016). BDV induced local C1q mRNA expression in the hippocampus and cortex (Dietzschold et al., 1995) and ZIKV infection enhanced expression of C1q and C3, associated with microglial activation and hippocampal synaptic damage and memory impairment in a murine infection model using ZIKV intracerebroventricular infusion (Figueiredo et al., 2019). In murine model induced by intracranial infection of WNV, C1q protein colocalized with microglia adjacent to WNV-infected neurons, possibly causing synaptic terminal loss (Vasek et al., 2016). These data suggest that local complement activation may induce cognitive impairment via the disruption of neurotransmission.

Some viruses increase their virulence by manipulating complement regulatory proteins. HSV-1 infection caused the down-regulation of FH in human primary neuroglia in vitro (Hill et al., 2009), potentially leading to enhanced activity of the alternative pathway. As suggested by studies using CD46 transgenic mice, CD46 is involved in the dissemination of measles virus into the CNS, increasing the risk of measles encephalitis (Rall et al., 1997; Manchester et al., 1999; Oldstone et al., 1999; Evlashev et al., 2000). In postmortem SSPE brain tissues, strong CD46 signal was observed on cerebral endothelium throughout the brain, as well as ependymal cells lining the ventricles and choroid plexus (McQuaid and Cosby, 2002), while CD46 expression was suppressed by measles virus infection in SSPE lesions (Ogata et al., 1997; McQuaid and Cosby, 2002). In addition, CD46 expression was observed in primary human glial cells (oligodendrocytes, astrocytes, and microglia) and CD46 inhibition by anti-CD46 antibody suppressed the fusion of glia and measles virus-infected T cells in vitro, suggesting that measles virus may spread in the brain parenchyma via binding to CD46 on glia (Cassiani-Ingoni et al., 2005). In HHV-6 infection models in vitro, using neuronal and glial cell lines, CD46 also mediated HHV-6 infection-induced transactivation of Multiple Sclerosis-Associated Retrovirus (MSRV) (Charvet et al., 2018). In a murine γ-herpesviruses infection model, C3 deficiency caused higher susceptibility to viral latency in the CNS (Kapadia et al., 2002). Several γ-herpesviruses encode homologues of RCAs (Farriesa and Atkinson, 1991), to inhibit complement activation (Fodor et al., 1995; Kapadia et al., 1999, 2002) thereby preventing complement-mediated elimination (Liszewski et al., 1996; Russo et al., 1996; Virgin et al., 1997). Like bacteria, some viruses can utilize and mimic host RCA proteins for their dissemination and entry into the CNS.

Sustained complement activation is associated with neuroinflammation and neurodegeneration in a number of neurological disorders (Eikelenboom et al., 1989; Rogers et al., 1992). Of note, COVID-19 patients reportedly suffer from diverse neurological complications (Stracciari et al., 2021). Although there is no direct evidence thus far to indicate causality between SARS-CoV-2 infection and neuropathology (Maury et al., 2021), future research will show whether there is a causal link between overactivation of complement in response to SARS-CoV-2 and neurological symptoms or long-term complications of COVID-19 (Garred et al., 2021).

Fungi

Fungal infection and dissemination into the brain has been proposed to contribute to the etiology of AD (Alonso et al., 2014, 2018). Candida is one of the most common commensal fungi, and can cause systemic infections which frequently affect the CNS (Lionakis et al., 2011; Alonso et al., 2014, 2018). Mice with invasive candidiasis exhibit microglial activation and local inflammation (Lionakis et al., 2011). Aspergillus and Cryptococcus are also fungal species that can cause invasive CNS infection, especially in immunocompromised individuals (Panackal and Williamson, 2015). Similarly, cerebral aspergillosis is caused by Aspergillus spp. that mainly affect immunocompromised individuals, such as AIDS patients and those under immunosuppressive treatment regimens (Ruhnke et al., 2007). Cryptococcosis, caused by the encapsulated fungus Cryptococcus neoformans, frequently occurs in AIDS, organ transplant recipients and cancer patients, and is the leading cause of mortality in immunocompromised individuals (Rajasingham et al., 2017). These fungal species can also cause meningoencephalitis (Gottfredsson and Perfect, 2000; Góralska et al., 2018), suggesting that fungal infection-induced local inflammation and meningoencephalitis may lead to long-term sequelae including cognitive dysfunction.

The complement system plays pivotal roles in the susceptibility to fungal CNS infection and infection-induced neuropathology (Table 1.3). A study using murine Candida albican infection models showed that C5 could be a major determinant of CNS infection susceptibility (Tuite et al., 2005). Neutrophils play a major protective role against dissemination of C. neoformans (Lovchik and Lipscomb, 1993; Graybill et al., 1997), and C5aR signaling is required for infection-induced neutrophil recruitment to the brain as suggested by data obtained in a murine infection model using C5 deficiency and inhibitory anti-C5aR antibodies (Sun et al., 2016). C5 and its cleavage product C5a are required for pulmonary accumulation of neutrophils upon infection and intravascular clearance of C. neoformans (Lovchik and Lipscomb, 1993; Sun et al., 2016), further confirming the crucial roles for C5 and C5a in neutrophil-mediated killing of C. neoformans. Jointly, these data suggest that complement activation and C5aR signaling are protective against C. neoformans-induced meningoencephalitis. In postmortem brain tissues from subjects with cerebral aspergillosis, C1q, C4, C3, and C5 were up-regulated in the brain, and co-localized with neurons, astrocytes, oligodendrocytes, and infiltrating macrophages (Rambach et al., 2008).

While the specific mechanistic links between fungal infection and dementia remain to be elucidated (Alonso et al., 2014, 2018), complement may be protective against neurodegenerative disorders via limiting fungal invasion into the CNS.

Parasites

Protozoan parasites including Toxoplasma gondii and Plasmodium spp. are obligate intracellular organisms that can potentially cause dysfunction and parenchymal injury in the brain. While T. gondii infects all nucleated cells of warm-blooded vertebrates, erythrocytes are the main target in Plasmodium infection in vertebrates. Host immune responses to these eukaryotes are very complex (Ivanova et al., 2019). The interactions between the complement system and these protozoa, with relevance for brain pathologies and the potential links to dementia, are summarized in Table 1.4.

Plasmodium

Plasmodium spp. are the agents causing malaria, one of the deadliest infectious diseases worldwide. Cerebral malaria (CM), caused by P. falciparum, is the most severe and life-threatening condition characterized by diffuse encephalopathy. CM is frequently accompanied by seizures and coma, and accounts for the majority of childhood deaths from malaria in endemic regions (Schmutzhard and Gerstenbrand, 1984; Idro et al., 2010; Riggle et al., 2020). In addition, more than 10% of children who survive CM have persistent neurological sequelae, including those affecting cognition and behavior (Frevert and Nacer, 2014). Among the features of CM is the adherence of Plasmodium-infected red blood cells (iRBCs) to brain vascular endothelium and BBB dysfunction (Yusuf et al., 2017; Pais and Penha-Gonçalves, 2019). Several mechanisms were suggested to explain the severe endothelial damage and vascular leakage in CM, and the proposed hypotheses include hemodynamic hypothesis (Van der Heyde et al., 2006; Wassmer and Grau, 2017), inflammation hypothesis (Silamut et al., 1999; Van der Heyde et al., 2006; Wassmer et al., 2006; Dunst et al., 2017), coagulation dysfunction hypothesis (Grau et al., 2003; Francischetti, 2008; Bridges et al., 2010; OSullivan et al., 2016), and innate immune hypothesis (Pais and Penha-Gonçalves, 2019). However, the exact mechanism remains elusive.

There is evidence suggesting that the complement system plays a significant role in CM pathogenesis. In an early study using murine CM model with P. berghei ANKA (Finley et al., 1982), T cell-deficient (nu/nu) mice were protected against CM compared to nu/+ mice, despite comparable parasitemia. The rapid decrease in serum C3 and concomitant increase in serum immune complexes observed in wildtype mice were absent in nu/nu mice, indicating the interaction between the complement system and cellular immunity in CM (Finley et al., 1982). C1q and C5 protein levels were also significantly higher in the brain of CM mice compared to non-CM mice, suggesting the activation of the classical pathway (Lackner et al., 2008). The roles for the complement system in CM were further examined using genetically modified mice, including mice deficient in C5 (Patel et al., 2008; Ramos et al., 2011; Buckingham et al., 2014), C5aR (Ramos et al., 2011; Kim et al., 2014; McDonald et al., 2015), C3 (Ramos et al., 2012), C4 (Ramos et al., 2012), FB (Ramos et al., 2012), and C3aR (Ramos et al., 2011). Notably, C5 deficient mice were fully protected from CM and CM-associated seizures (Ramos et al., 2011; Buckingham et al., 2014), while C5aR deficient mice were only moderately protected (Ramos et al., 2011; Kim et al., 2014). Mice lacking FB, C4, or C3aR showed outcomes comparable to wildtype mice (Ramos et al., 2011, 2012). In addition, C9 deposits were observed in the CNS during CM, and C9 inhibition (neutralizing anti-C9 antibody injection) significantly delayed CM development (Ramos et al., 2011). Results from clinical studies also show complement activation during CM. Serum C5a levels were significantly higher in children with CM compared to those without CM (Kim et al., 2014). Postmortem CM frontal lobes exhibited activation of complement, the coagulation cascade, and platelets (Kumar et al., 2018). These data suggest that MAC formation plays a critical role in CM pathogenesis. In addition, persistent cognitive deficits caused in the offspring by in utero exposure to malaria were dependent on maternal C5a-C5aR signaling (McDonald et al., 2015). These findings point to the role of C5a in the initiation of neuroinflammation together with the dysregulation of angiogenesis and synaptogenesis (McDonald et al., 2013). Surprisingly, the formation of conventional C5 convertase via C3 activation was not required for CM progression (Ramos et al., 2012), which suggests that C5 was activated by coagulation factors or other non-complement proteases (Ramos et al., 2012; Figure 2). These observations support the role for the complement system as a link between immune responses and dysregulated coagulation during CM.

FIGURE 2

The interactions between Plasmodium and the complement system are possibly even more intricate (Schmidt et al., 2015; Kennedy et al., 2016, 2017; Rosa et al., 2016). Blood stage P. falciparum (free merozoites as well as intraerythrocytic schizonts) evades complement-mediated destruction by recruiting FH, a major negative regulator of complement activation, on the cell surface (Kennedy et al., 2016; Rosa et al., 2016). As mentioned above, several other pathogens, including Neisseria meningitidis (Granoff et al., 2009; Schneider et al., 2009) and Borrelia burgdorferi (Kraiczy et al., 2001), use FH for the same purpose, suggesting that it is an evolutionarily conserved strategy to circumvent complement-mediated elimination. Plasmodium utilizes another complement regulatory protein CR1 as a receptor for red blood cell invasion (Tham et al., 2010; Spadafora et al., 2010). In addition, mobilization of CR1 on the surface of Plasmodium-infected red blood cells is required for rosetting (Rowe et al., 1997), a process implicated in vascular obstruction during severe malaria (Carlson, 1993). CR1 polymorphisms could explain the association between altered efficiency of rosetting and malaria severity (Cockburn et al., 2004; Schmidt et al., 2015).

In conclusion, overactivation of complement cascade triggered by the parasite conceivably contributes to CM pathogenesis, and the inhibition of the complement cascade at the level or downstream of C5 activation, and/or the inhibition of CR1 could be a beneficial treatment strategy for CM.

Toxoplasma gondii

Toxoplasma gondii infects approximately one-third of the world population. It is an opportunistic infection that in individuals with immunodeficiency can cause severe diseases, including Toxoplasma encephalitis (Marra, 2018). Infection during pregnancy can lead to congenital toxoplasmosis, the severity of which depends on the stage of pregnancy (Bigna et al., 2020). While Toxoplasma rarely causes symptoms in healthy individuals with effective immunity, it can establish latent infection in the brain and other tissues (Pittman and Knoll, 2015). It is also notable that the virulence can vary depending on Toxoplasma genotype (Howe and Sibley, 1995; Behnke et al., 2011; Pomares et al., 2018; Taniguchi et al., 2018). Once disseminated into the brain, the parasite transforms into bradyzoite form (cyst) and establishes a life-long infection in neurons and glia (Ólafsson and Barragan, 2020). The presence of Toxoplasma cysts in the CNS has been linked to various neuropsychiatric disorders, such as schizophrenia (Elsheikha et al., 2016; Del Grande et al., 2017; Fuglewicz et al., 2017; Fond et al., 2018; Stepanova et al., 2019; Tyebji et al., 2019a, b), possibly via the direct modulation of dopaminergic/serotonergic signaling as well as neuroinflammation (Henriquez et al., 2009; Mahmoud et al., 2017). T cells and type II interferon (IFN-γ)-dependent immune responses are an essential part of the host defense against Toxoplasma infection (Sasai et al., 2018). Type I interferons (IFNs) also play an important regulatory role in the innate immune response during protozoan infection, including toxoplasmosis (Silva-Barrios and Stäger, 2017).

Toxoplasma is classified into three groups: virulent type I, which causes acute infection, and avirulent type II and type III, which are responsible for chronic infection. Several studies have suggested the involvement of the complement system during acute Toxoplasma (type I) infection. Toxoplasma lytic activity of human sera was dependent on classical pathway components (C1q, C2, C4, C5, C6, C7, and C8) in a study using a virulent Toxoplasma strain in vitro (Schreiber and Feldman, 1980). Animal sera (pig, rabbit, and dog), with the exception of cat serum, effectively killed Toxoplasma tachyzoites of a virulent strain via C1q and natural IgM-dependent complement activation (Kaneko et al., 2004). Toxoplasma tachyzoites of the same strain were resistant to complement-mediated lysis via the formation of iC3b, the inactive form of C3b (Fuhrman and Joiner, 1989). Toxoplasma tachyzoites of both virulent and avirulent strains mobilized complement regulatory proteins (FH and C4BP) on their surface to evade complement-mediated parasite killing in vitro, whereas C3 deficient mice suffered higher parasite burden in the brain and other organs in vivo, suggesting complex host-parasite interactions (Sikorski et al., 2020). Of note, C5 deficiency rendered either protection or enhanced mortality depending on the genetic background of the murine host (Araujo et al., 1975). These data suggest that, while the complement system plays a pivotal role in the protection against acute Toxoplasma infection, the parasite has evolved strategies to manipulate the complement system to survive and propagate in the host.

The interaction between Toxoplasma and the complement system in the brain has recently been elucidated. In murine Toxoplasma infection models, cerebral C1q is upregulated during chronic infection with virulent and avirulent strains (Xiao et al., 2016), and persistent infection with a virulent Toxoplasma strain led to the upregulation of C1q, C1r, C3, and C4 mRNA levels and deposition of complement component proteins (C1q and C3) in the brain. These changes were associated with neurodegeneration (Li et al., 2019). An avirulent Toxoplasma strain also caused upregulation of complement proteins, including C3, C4b, and C1q, in the mouse brain (Huang et al., 2019). Furthermore, mRNAs for FB and FP, C3aR, and C5aR were up-regulated in the brain of mice chronically infected with an avirulent Toxoplasma strain (Shinjyo et al., 2021), suggesting that the alternative pathway is activated in the brain during chronic infection. The Toxoplasma infection-induced up-regulation of FB, FP, and C5aR mRNAs occurred in primary murine glial cells in vitro in a microglia-dependent manner (Shinjyo et al., 2021). These data suggest that, while complement-dependent clearance is essential in the initial, peripheral phase of infection, chronic Toxoplasma infection can cause persistent complement activation in the CNS.

Prion Proteins

Transmissible spongiform encephalopathies (TSEs, prion diseases) are fatal neurodegenerative diseases, which include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goat, Creutzfeldt-Jakob disease (CJD), fatal familial insomnia, and Gerstmann-Sträussler-Scheinker syndrome in humans (Prusiner et al., 1998; Prusiner, 1998). Most neurodegenerative diseases, including prion diseases and AD, share two common features: the accumulation and self-propagation of misfolded proteins (Gomez-Gutierrez and Morales, 2020). TSE-causing infectious prion proteins (PrP^Sc) transmit the disease-associated conformation to normal prion proteins (PrP^C), leading to further propagation of PrP^Sc. Following peripheral exposure and prior to neuroinvasion, PrP^Sc accumulates in lymphoid tissues, including lymph nodes and Peyer’s patches. Early PrP^Sc accumulation occurs within the germinal center on follicular dendritic cells (FDCs) (Brown et al., 1999) as well as within tingible body macrophages (McGovern and Jeffrey, 2007). From the lymphoid tissues, transmission to the CNS occurs via the peripheral nervous system (Glatzel et al., 2001). The central event in prion disease progression is the accumulation of PrP^Sc in the CNS accompanied by neuronal loss and spongiform neuropils, suggesting aggressive destruction of neural networks (Budka, 2000).

The involvement of the complement system in prion-induced neuropathology has been observed in different types of prion diseases (Bonifati and Kishore, 2007; Table 1.5). In scrapie-infected rodents, total complement activity in the brain was significantly increased at the terminal stage (Lv et al., 2014). In addition, C1q upregulation (Dandoy-Dron et al., 1998, 2000; Carroll et al., 2018), C3 upregulation and colocalization with neurons, and MAC deposition on neurons were observed in infected human brain (Kovacs et al., 2004) as well as in scrapie model in mice (Lv et al., 2014), suggesting the activation of the classical and terminal pathways. C1q also colocalized with infected neurons in vitro, and throughout the brain C1q distribution overlapped with PrP (Hasebe et al., 2012). In addition, FB and FP levels significantly increased in the brain of scrapie-infected mice, while FB and C3 colocalized with neurons and activated microglia (Chen et al., 2020), suggesting the activation of the alternative pathway and microglia. Notably, mice deficient in C1q or FB/C2 were protected against encephalopathy after intraperitoneal prion exposure, but C3 deficiency was not protective (Klein et al., 2001). Interestingly, reactive astrocytes in prion diseases are characterized by C3 up-regulation and mixed A1/A2 phenotype (Hartmann et al., 2019) distinct from neurotoxic astrocytes observed in other neurodegenerative diseases (Kwon and Koh, 2020). The abolishment of C3-positive astrocytes led to prion disease acceleration (Hartmann et al., 2019). These data suggest that C3 plays multiple roles in prion disease progression, depending on the context. In contrast, complement hemolytic activity was significantly lower in the CSF of CJD patients, particularly in genetic CJD cases (Chen et al., 2016). In addition, the protein levels of some complement components, including C3, C4, and C9, decreased in the CSF of sporadic CJD (sCJD) patients compared to non-CJD group (Chen et al., 2016). While the explanation conceivably lies in the increased consumption of complement in the brain parenchyma, the neuropathologic implications of these findings are currently elusive.

Given that FH deficiency was protective against PrP propagation (Kane et al., 2017), prion proteins may escape complement-mediated clearance by manipulating FH-dependent complement inhibition, possibly via direct interaction between PrP^Sc and FH (Kane et al., 2017). Thus, RCAs seem important target molecules exploited by infectious agents, including prion proteins, to evade innate immunity and propagate throughout the body including the CNS.

Complement: A Double Edge Sword in the Infected Brain

The consequences of local complement activation by infectious agents for brain tissue integrity and function are highly context dependent. Complement has a role in the regulation of normal neuronal functioning and homeostasis. It may be neuroprotective and play a critical role in the elimination of various pathogens, but can also be a major mediator of neurodegeneration and tissue damage. The complement system can also be hijacked by some pathogens and play a complicit role in their dissemination. Figure 2 illustrates the potential interactions between the complement system and infectious agents, and Table 2 summarizes the responses of selected complement proteins to the individual pathogens, including up- or down-regulation, deposition, and the impact of genetic polymorphism or genetic manipulations.

In the CNS, C1q plays potentially harmful roles in bacterial (S. pneumoniae-induced bacterial meningitis) (Zwijnenburg et al., 2007), viral (HIV-associated cognitive impairment) (McGuire et al., 2016), parasite (Plasmodium, CM) (Lackner et al., 2008), and prion (Klein et al., 2001) infections, while it may be protective during the initial phase of prion disease (Flores-Langarica et al., 2009). Jointly these findings indicate the deleterious consequences of overactivation of the classical pathway. The lectin pathway is protective against herpes simplex virus encephalitis by inhibiting viral dissemination into the CNS (Bibert et al., 2019). While C3-mediated pathogen clearance is beneficial in the periphery (Mehlhop et al., 2005; Brooke et al., 2012; Sun et al., 2016), C3d deposition on synaptic terminals may facilitate synaptic loss in WNV infection (Vasek et al., 2016). Likewise, the net outcome of downstream complement activation seems to be context-dependent. C5 is important for fungal clearance in the vasculature (Sun et al., 2016) and inhibits fungal dissemination into the CNS (Tuite et al., 2005). In contrast, in the Plasmodium infection, C5 deficiency is protective against CM (Patel et al., 2008; Ramos et al., 2011; Buckingham et al., 2014). Inhibition of MAC formation was also protective against CM (Ramos et al., 2011), confirming the crucial role of terminal complement pathway in CM pathogenesis. C3aR was up-regulated in the brain upon viral infection (Libbey et al., 2017) and C3aR deficiency was protective against viral infection-induced synaptic loss (Vasek et al., 2016). C5aR deficiency was also protective against CM development (Patel et al., 2008; Kim et al., 2014; McDonald et al., 2015), as well as bacterial meningitis (Woehrl et al., 2011). However, neither C3aR deficiency nor C5aR deficiency were protective against prion-induced neuropathology (Carroll et al., 2018), indicating pathogen-specific roles of anaphylatoxin receptors in the CNS.

CD46, a negative regulator of the classical and lectin pathways, aids in the dissemination of bacteria (N. meningitidis) (Johansson et al., 2003, 2005) and viruses [Measles virus (Rall et al., 1997; Manchester et al., 1999; Oldstone et al., 1999; Evlashev et al., 2000) and HHV-6 (Cassiani-Ingoni et al., 2005)] into the CNS, leading to meningitis and encephalitis, respectively. While the use of CD46 by these pathogens could be an evasion strategy from the classical or lectin pathway-mediated clearance, CD46-dependent facilitation of immune cell infiltration into the CNS (Manchester et al., 1999; Oldstone et al., 1999) and cell-cell fusion of infected lymphocytes and glial cells (Cassiani-Ingoni et al., 2005) suggest higher mechanistic complexity of the interactions between complement and infectious agents. FH, a negative regulator of the alternative pathway, is also engaged in the dissemination of pathogens in bacterial (S. suis) (Kong et al., 2017) and prion infections (Kane et al., 2017), indicating that these infectious agents manipulate the alternative complement pathway for their propagation in the brain. The fact that a viral RCA homolog plays a facilitatory role in viral dissemination via the inhibition of C3-dependent host defense (Kapadia et al., 2002) suggests that infectious agents have evolved diverse molecular mechanisms to escape complement-mediated killing.

Discussion

Potential Link Between Infection-Induced Complement Activation and Dementia

Considering the link between cognitive impairment and aberrant complement activation in the CNS (Aiyaz et al., 2012; Rubio-Perez and Morillas-Ruiz, 2012), the most simplified view is that CNS infection could lead to dementia via the complement activation (Figure 3A: dotted rectangle). However, as discussed above, the mechanistic links between infectious agents, complement, and neurodegeneration are far more complex. Due to the multiple neurodevelopmental and homeostatic functions that the complement system and its individual components play in the brain (Figure 1), complement activation by infectious agents can cause an imbalance in the intricate web of interactions between complement proteins and the nervous system with deleterious consequences for CNS tissue integrity and function (Figure 3B: solid rectangle). This could explain the unpredictable and sometimes inconsistent observations in different studies in human patients as well as in animal models of CNS infection. The multiple functions of the complement system in the CNS together with the complexity of immune responses to infection call for well-informed and highly selective approaches when manipulating the complement system for therapeutic benefit. For example, inhibiting the down-stream of complement cascade (C5 and MAC) and/or C5aR could protect the brain from Plasmodium infection-induced tissue damage (Patel et al., 2008; Ramos et al., 2011; Buckingham et al., 2014; Kim et al., 2014), whereas inhibition restricted to the upstream components (C1q, C2, and FB) could be beneficial in prion diseases (Klein et al., 2001), as shown in animal models. However, these studies were conducted using constitutive inactivation of specific genes. As the complement system plays multiple roles in the CNS, roles which are distinct from those in the periphery, it is imperative to investigate CNS-specific roles of the complement system in the context of an infection by a specific pathogen. Furthermore, while complement proteins are locally produced in the brain, it is less clear which cell types are responsible, how complement protein production and responses are regulated, and how are these processes influenced by various stimuli under physiological and pathological conditions, including CNS infection. Of particular interest in this respect are the potential functions of intracellular C3 (Elvington et al., 2016), not only with regard to the interactions between infectious agents and the brain-resident cells but also the role of intracellular C3 in neurodegeneration. Considering the diverse roles of glial cells (astrocytes and microglia, the brain-resident macrophages) in the maintenance of CNS homeostasis, further studies are required to elucidate how infectious agents modulate complement generation in glial cells and how, in turn, it might affect the phenotypes of these cells.

FIGURE 3

Conclusion

Of the approximately 50 million people with dementia worldwide, about 50% live in low- and middle-income countries (WHO, 2019). Considering higher risk of infection and infection-induced brain disorders in those countries (Fernandes and Caramelli, 2019; Singh et al., 2020), understanding of the potential mechanistic links between infection and neurodegenerative disorders including dementia, will inform the development of preventive and therapeutic strategies. While amyloidogenesis is widely accepted as the underlying cause of AD and other forms of neurodegenerative diseases, Aβ-targeting drug development has been so far unsuccessful (Robakis, 2020). Given that the presence of amyloid plaques does not necessarily indicate cognitive decline (Skaper, 2012; Robakis, 2020), alternative culprits and theories are needed. Indeed, there is a growing body of evidence showing that innate immunity and neuroinflammation play a pivotal role in dementia development (Leng and Edison, 2020).

Separated from the other parts of the body by the BBB and CSF barrier, the CNS is uniquely protected by special immune components, including the complement system and glial cells. While locally produced complement components play crucial homeostatic roles in the CNS, dysregulated complement activity could be detrimental to the function of the CNS. As the key element of brain-resident innate immunity, the complement system plays both protective and destructive roles in neurodegeneration (Kolev et al., 2009). Whereas aberrant complement activation is frequently associated with neuroinflammation and neurodegenerative disorders, the complement system exerts homeostatic functions via eliminating apoptotic cells, cell debris, and toxic substances, and supports plasticity and tissue repair. A broad range of infectious agents can potentially interact with the complement system in the brain and the net outcome of these interactions appears to depend on the specific pathogens, the target components, and the mode of interaction. It is therefore conceivable that pathogen-triggered and persistent activation of the complement system represents the missing mechanistic link between infection, in particular infection affecting the CNS, and neurodegeneration. We are fully aware that the simplified view presented in Figure 3 does not capture every aspect of the involvement of the complement system in infection-induced neuropathology and neurodegeneration, but only highlights the key components of the interplay between pathogens and complement activation induced–neurodegenerative processes that may lead to dementia. While the specific mechanistic links between CNS infection, neurodegeneration and dementia are still unclear, the involvement of the complement system and the pathogen- and disease stage-specific roles of the individual complement proteins warrant further intense investigation.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  AiyazM.LuptonM.ProitsiP.PowellJ.LovestoneS. (2012). Complement activation as a biomarker for Alzheimer’s disease.Immunobiology217204–215. 10.1016/j.imbio.2011.07.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  AlonsoR.MarinaD.MoratoA.RábanoE.CarrascoA.PisaL. (2014). Fungal infection in patients with Alzheimer’s disease.J. Alzheimers Dis.41301–311. 10.3233/JAD-132681

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  AlonsoR.PisaD.Fernández-FernándezA.CarrascoL. (2018). Infection of fungi and bacteria in brain tissue from elderly persons and patients with Alzheimer’s disease.Front. Aging Neurosci.10:159. 10.3389/fnagi.2018.00159

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  Alvarez-LafuenteR.García-MontojoM.De las HerasV.BartoloméM.ArroyoR. (2006). Clinical parameters and HHV-6 active replication in relapsing–remitting multiple sclerosis patients.J. Clin. Virol.37S24–S26. 10.1016/S1386-6532(06)70007-5

  • CrossRef
  • Google Scholar

• 5

  AmaraU.FlierlM.RittirschD.KlosA.ChenH.AckerB.et al (2010). Molecular interacommunication between the complement and coagulation systems.J. Immunol.1855628–5636. 10.4049/jimmunol.0903678

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  AndrewsJ.Cho-ParkY.FerryJ.AbramsonJ.RobbinsG. (2011). Kaposi’s sarcoma-associated herpesvirus-related solid lymphoma involving the heart and brain.AIDS Res. Treat.2011:729854. 10.1155/2011/729854

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  AraujoF.RosenbergL.RemingtonJ. (1975). Experimental Toxoplasma gondii infection in mice: the role of the fifth component of complement.Proc. Soc. Exp. Biol. Med.149800–804. 10.3181/00379727-149-38902

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  ArmahH.WangG.OmaluB.TeshR.GyureK.ChuteD.et al (2007). Systemic distribution of West Nile virus infection: postmortem immunohistochemical study of six cases.Brain Pathol.17354–362. 10.1111/j.1750-3639.2007.00080.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  AvalosC.AbreuC.QueenS.LiM.PriceS.ShirkE.et al (2017). Brain macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir.mBio8:e01186-17. 10.1128/mBio.01186-17

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  BaldiniF.BaiocchiniA.SchininàV.AgratiC.GiancolaM.AlbaL.et al (2013). Brain localization of Kaposi’s sarcoma in a patient treated by combination antiretroviral therapy.BMC Infect Dis.13:600. 10.1186/1471-2334-13-600

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  BarnumS.AmesR.MaycoxP.HadinghamS.MeakinJ.HarrisonD.et al (2002). Expression of the complement C3a and C5a receptors after permanent focal ischemia: an alternative interpretation.Glia38169–173. 10.1002/glia.10069

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  BehnkeM.KhanA.WoottonJ.DubeyJ.TangK.SibleyL. (2011). Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinases.Proc. Natl. Acad. Sci. U.S.A.1089631–9636. 10.1073/pnas.1015338108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  BiD.QiaoL.BergelsonI.EkC.DuanL.ZhangX.et al (2015). Staphylococcus epidermidis bacteremia induces brain injury in neonatal mice via toll-like receptor 2-dependent and -independent pathways.J. Infect. Dis.2121480–1490. 10.1093/infdis/jiv231

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  BibertS.PiretJ.QuinodozM.CollinetE.ZoeteV.MichielinO.et al (2019). Herpes simplex encephalitis in adult patients with MASP-2 deficiency.PLoS Pathog.15:e1008168. 10.1371/journal.ppat.1008168

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  BignaJ.TochieJ.TounougaD.BekoloA.YmeleN.YoudaE.et al (2020). Global, regional, and country seroprevalence of Toxoplasma gondii in pregnant women: a systematic review, modelling and meta-analysis.Sci. Rep.10:12102. 10.1038/s41598-020-69078-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  BonifatiD.KishoreU. (2007). Role of complement in neurodegeneration and neuroinflammation.Mol. Immunol.44999–1010. 10.1016/j.molimm.2006.03.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  BossolascoS.FalkK.PonzoniM.CeseraniN.CrippaF.LazzarinA.et al (2006). Ganciclovir is associated with low or undetectable Epstein-Barr virus DNA load in cerebrospinal fluid of patients with HIV-related primary central nervous system lymphoma.Clin. Infect. Dis.42e21–e25.

  • Google Scholar

• 18

  BrennanF.JogiaT.GillespieE.BlomsterL.LiX.NowlanB.et al (2019). Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2.JCI Insight4:e98254. 10.1172/jci.insight.98254

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  BridgesD.BunnJ.van MourikJ.GrauG.PrestonR.MolyneuxM. (2010). Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings.Blood1151472–1474. 10.1182/blood-2009-07-235150

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  Brito FerreiraM.Antunes de BritoC.MoreiraÁde Morais MachadoM.Henriques-SouzaA.CordeiroM.et al (2017). Guillain-Barré syndrome, acute disseminated encephalomyelitis and encephalitis associated with zika virus infection in Brazil: detection of viral RNA and isolation of virus during late infection.Am. J. Trop. Med. Hyg.971405–1409. 10.4269/ajtmh.17-0106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  BrookeC.SchäferA.MatsushimaG.WhiteL.JohnstonR. (2012). Early activation of the host complement system is required to restrict central nervous system invasion and limit neuropathology during Venezuelan equine encephalitis virus infection.J. Gen. Virol.93797–806. 10.1099/vir.0.038281-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  BrouwerM.de GansJ.HeckenbergS.ZwindermanA.van der PollT.van de BeekD. (2009). Host genetic susceptibility to pneumococcal and meningococcal disease: a systematic review and meta-analysis.Lancet Infect. Dis.931–44. 10.1016/S1473-3099(08)70261-5

  • CrossRef
  • Google Scholar

• 23

  BrownK.StewartK.RitchieD.MabbottN.WilliamsA.FraserH.et al (1999). Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells.Nat. Med.51308–1312. 10.1038/15264

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  BuckinghamS.RamosT.BarnumS. (2014). Complement C5-deficient Mice are protected from seizures in experimental cerebral malaria.Epilepsia55e139–e142.

  • Google Scholar

• 25

  BudkaH. (2000). Histopathology and immunohistochemistry of human transmissible spongiform encephalopathies (TSEs).Arch. Virol. Suppl.16135–142. 10.1007/978-3-7091-6308-5_12

  • CrossRef
  • Google Scholar

• 26

  CadmanE.PuttfarckenP. (1997). Beta-amyloid peptides initiate the complement cascade without producing a comparable effect on the terminal pathway in vitro.Exp. Neurol.146388–394. 10.1006/exnr.1997.6540

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  CarboneI.LazzarottoT.IanniM.PorcelliniE.FortiP.MasliahE.et al (2014). Herpes virus in Alzheimer’s disease: relation to progression of the disease.Neurobiol. Aging35122–129. 10.1016/j.neurobiolaging.2013.06.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  CarlsonJ. (1993). Erythrocyte rosetting in Plasmodium falciparum malaria–with special reference to the pathogenesis of cerebral malaria.Scand. J. Infect. Dis. Suppl.861–79.

  • Google Scholar

• 29

  CarrollJ.RaceB.WilliamsK.ChesebroB. (2018). Toll-like receptor 2 confers partial neuroprotection during prion disease.PLoS One13:e0208559. 10.1371/journal.pone.0208559

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  Cassiani-IngoniR.GreenstoneH.DonatiD.Fogdell-HahnA.MartinelliE.RefaiD.et al (2005). CD46 on glial cells can function as a receptor for viral glycoprotein-mediated cell-cell fusion.Glia52252–258. 10.1002/glia.20219

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  CharvetB.ReynaudJ.Gourru-LesimpleG.PerronH.MarcheP.HorvatB. (2018). Induction of proinflammatory multiple sclerosis-associated retrovirus envelope protein by human herpesvirus-6A and CD46 receptor engagement.Front. Immunol.9:2803. 10.3389/fimmu.2018.02803

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  ChenC.LvY.HuC.XuX.ZhangR.XiaoK.et al (2020). Alternative complement pathway is activated in the brains of scrapie-infected rodents.Med. Microbiol. Immunol.20981–94. 10.1007/s00430-019-00641-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  ChenC.LvY.ShiQ.ZhouW.XiaoK.SunJ.et al (2016). Low activity of complement in the cerebrospinal fluid of the patients with various prion diseases.Infect. Dis. Poverty5:35. 10.1186/s40249-016-0128-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  ClarkeP.LeserJ.QuickE.DionneK.BeckhamJ.TylerK. (2014). Death receptor-mediated apoptotic signaling is activated in the brain following infection with West Nile virus in the absence of a peripheral immune response.J. Virol.881080–1089. 10.1128/JVI.02944-13

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  CliffordD. (2017). HIV-associated neurocognitive disorder.Curr. Opin. Infect. Dis.30117–122. 10.1097/QCO.0000000000000328

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  CockburnI.MackinnonM.O’DonnellA.AllenS.MouldsJ.BaisorM.et al (2004). A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria.Proc. Natl. Acad. Sci. U.S.A.101272–277. 10.1073/pnas.0305306101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  CoulthardL.HawksworthO.ConroyJ.LeeJ.WoodruffT. (2018). Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance.Mol. Immunol.101176–181. 10.1016/j.molimm.2018.06.271

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  CoulthardL.WoodruffT. (2015). Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth.J. Immunol.1943542–3548. 10.4049/jimmunol.1403068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  CzirrE.CastelloN.MosherK.CastellanoJ.HinksonI.LucinK.et al (2017). Microglial complement receptor 3 regulates brain Abeta levels through secreted proteolytic activity.J. Exp. Med.2141081–1092. 10.1084/jem.20162011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  Dandoy-DronF.BenboudjemaL.GuilloF.JaeglyA.JasminC.DormontD.et al (2000). Enhanced levels of scrapie responsive gene mRNA in BSE-infected mouse brain.Brain Res. Mol. Brain Res.76173–179. 10.1016/s0169-328x(00)00028-0

  • CrossRef
  • Google Scholar

• 41

  Dandoy-DronF.GuilloF.BenboudjemaL.DeslysJ.LasmézasC.DormontD.et al (1998). Gene expression in scrapie. Cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mRNA transcripts.J. Biol. Chem.2737691–7697. 10.1074/jbc.273.13.7691

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  DavilaS.WrightV.KhorC.SimK.BinderA.BreunisW.et al (2010). Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.Nat. Genet.42772–776. 10.1038/ng.640

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  Del GrandeC.GalliL.SchiaviE.Dell’OssoL.BruschiF. (2017). Is Toxoplasma gondii a trigger of bipolar disorder?Pathogens6:3. 10.3390/pathogens6010003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  DempseyP.AllisonM.AkkarajuS.GoodnowC.FearonD. (1996). C3d of complement as a molecular adjuvant: bridging innate and acquired immunity.Science271348–350. 10.1126/science.271.5247.348

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  DepboyluC.SchäferM.SchwaebleW.ReinhartT.MaedaH.MitsuyaH.et al (2005). Increase of C1q biosynthesis in brain microglia and macrophages during lentivirus infection in the rhesus macaque is sensitive to antiretroviral treatment with 6-chloro-2′,3′-dideoxyguanosine.Neurobiol. Dis.2012–26. 10.1016/j.nbd.2005.01.030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  DietzscholdB.SchwaebleW.SchäferM.HooperD.ZehngY.PetryF.et al (1995). Expression of C1q, a subcomponent of the rat complement system, is dramatically enhanced in brains of rats with either Borna disease or experimental allergic encephalomyelitis.J. Neurol. Sci.13011–16. 10.1016/0022-510x(94)00269-t

  • CrossRef
  • Google Scholar

• 47

  Dominguez-PunaroM.SeguraM.PlanteM.LacoutureS.RivestS.GottschalkM. (2007). Streptococcus suis serotype 2, an important swine and human pathogen, induces strong systemic and cerebral inflammatory responses in a mouse model of infection.J. Immunol.1791842–1854. 10.4049/jimmunol.179.3.1842

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  DunstJ.KamenaF.MatuschewskiK. (2017). Cytokines and chemokines in cerebral malaria pathogenesis.Front. Cell Infect. Microbiol.7:324. 10.3389/fcimb.2017.00324

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  EikelenboomP.BateC.Van GoolW.HoozemansJ.RozemullerJ.VeerhuisR.et al (2002). Neuroinflammation in Alzheimer’s disease and prion disease.Glia40232–239. 10.1002/glia.10146

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  EikelenboomP.HackC.RozemullerJ.StamF. (1989). Complement activation in amyloid plaques in Alzheimer’s dementia.Virchows Arch. B Cell Pathol. Incl. Mol. Pathol.56259–262. 10.1007/BF02890024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  ElsheikhaH.BüsselbergD.ZhuX. (2016). The known and missing links between Toxoplasma gondii and schizophrenia.Metab. Brain Dis.31749–759. 10.1007/s11011-016-9822-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  ElvingtonM.LiszewskiM.AtkinsonJ. (2016). Evolution of the complement system: from defense of the single cell to guardian of the intravascular space.Immunol. Rev.2749–15. 10.1111/imr.12474

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  EvlashevA.MoyseE.ValentinH.AzocarO.Trescol-BiémontM.MarieJ.et al (2000). Productive measles virus brain infection and apoptosis in CD46 transgenic mice.J. Virol.741373–1382. 10.1128/jvi.74.3.1373-1382.2000

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  FarriesaT.AtkinsonJ. (1991). Evolution of the complement system.Immunol. Today12295–300. 10.1016/0167-5699(91)90002-B

  • CrossRef
  • Google Scholar

• 55

  FernandesB.CaramelliP. (2019). Ischemic stroke and infectious diseases in low-income and middle-income countries.Curr. Opin. Neurol.3243–48. 10.1097/WCO.0000000000000641

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  FigueiredoC.Barros-AragãoF.NerisR.FrostP.SoaresC.SouzaI.et al (2019). Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice.Nat. Commun.10:3890. 10.1038/s41467-019-11866-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  FijenC.van den BogaardR.SchipperM.MannensM.SchlesingerM.NordinF.et al (1999). Properdin deficiency: molecular basis and disease association.Mol. Immunol.36863–867. 10.1016/s0161-5890(99)00107-8

  • CrossRef
  • Google Scholar

• 58

  FinleyR.MackeyL.LambertP. (1982). Virulent P. berghei malaria: prolonged survival and decreased cerebral pathology in cell-dependent nude mice.J. Immunol.12192213–2218.

  • Google Scholar

• 59

  Flores-LangaricaA.SebtiY.MitchellD.SimR.MacPhersonG. (2009). Scrapie pathogenesis: the role of complement C1q in scrapie agent uptake by conventional dendritic cells.J. Immunol.1821305–1313. 10.4049/jimmunol.182.3.1305

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  FodorW.RollinsS.Bianco-CaronS.RotherR.GuilmetteE.BurtonW.et al (1995). The complement control protein homolog of herpesvirus saimiri regulates serum complement by inhibiting C3 convertase activity.J. Virol.693889–3892. 10.1128/JVI.69.6.3889-3892.1995

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  FondG.BoyerL.SchürhoffF.BernaF.GodinO.BulzackaE.et al (2018). Latent Toxoplasma infection in real-world schizophrenia: results from the national FACE-SZ cohort.Schizophr Res.S0920, 30262–30265. 10.1016/j.schres.2018.05.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  FrancischettiI. (2008). Does activation of the blood coagulation cascade have a role in malaria pathogenesis?Trends Parasitol.24258–263. 10.1016/j.pt.2008.03.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  FrevertU.NacerA. (2014). Fatal cerebral malaria: a venous efflux problem.Front. Cell Infect. Microbiol.4:155. 10.3389/fcimb.2014.00155

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  FuH.LiuB.FrostJ.HongS.JinM.OstaszewskiB.et al (2012). Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia.Glia60993–1003. 10.1002/glia.22331

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  FuglewiczA.PiotrowskiP.StodolakA. (2017). Relationship between toxoplasmosis and schizophrenia: a review.Adv. Clin. Exp. Med.261031–1036.

  • Google Scholar

• 66

  FuhrmanS.JoinerK. (1989). Toxoplasma gondii: mechanism of resistance to complement-mediated killing.J. Immunol.142940–947.

  • Google Scholar

• 67

  GarredP.TennerA.MollnesT. (2021). Therapeutic targeting of the complement system: from rare diseases to pandemics.Pharmacol. Rev.73792–827. 10.1124/pharmrev.120.000072

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  GasqueP.DeanY.McGrealE.VanBeekJ.MorganB. (2000). Complement components of the innate immune system in health and disease in the CNS.Immunopharmacology49171–186. 10.1016/s0162-3109(00)80302-1

  • CrossRef
  • Google Scholar

• 69

  GasqueP.SinghraoS. K.NealJ. W.WangP.SayahS.FontaineM.et al (1998). The receptor for complement anaphylatoxin C3a is expressed by myeloid cells and nonmyeloid cells in inflamed human central nervous system: analysis in multiple sclerosis and bacterial meningitis.J. Immunol.1603543–3554.

  • Google Scholar

• 70

  GlatzelM.HeppnerF.AlbersK.AguzziA. (2001). Sympatheticinnervation of lymphoreticular organs is rate limiting for prion neuroinvasion.Neuron3125–34. 10.1016/s0896-6273(01)00331-2

  • CrossRef
  • Google Scholar

• 71

  Gomez-GutierrezR.MoralesR. (2020). The prion-like phenomenon in Alzheimer’s disease: evidence of pathology transmission in humans.PLoS Pathog.16:e1009004. 10.1371/journal.ppat.1009004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  GóralskaK.BlaszkowskaJ.DzikowiecM. (2018). Neuroinfections caused by fungi.Infection46443–459. 10.1007/s15010-018-1152-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  GorelikA.SapirT.Haffner-KrauszR.OlenderT.WoodruffT.ReinerO. (2017). Developmental activities of the complement pathway in migrating neurons.Nat. Commun.8:15096. 10.1038/ncomms15096

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  GottfredssonM.PerfectJ. (2000). Fungal meningitis.Semin. Neurol.20307–322. 10.1055/s-2000-9394

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  GranoffD.WelschJ.RamS. (2009). Binding of complement factor H (fH) to Neisseria meningitidis is specific for human fH and inhibits complement activation by rat and rabbit sera.Infect. Immun.77764–769. 10.1128/IAI.01191-08

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  GrauG.MackenzieC.CarrR.RedardM.PizzolatoG.AllasiaC.et al (2003). Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria.J. Infect. Dis.187461–466. 10.1086/367960

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  GraybillJ.BocanegraR.LambrosC.LutherM. (1997). Granulocyte colony stimulating factor therapy of experimental cryptococcal meningitis.J. Med. Vet. Mycol.35243–247. 10.1080/02681219780001221

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  GriffinD. (2020). Measles virus persistence and its consequences.Curr. Opin. Virol.4146–51. 10.1016/j.coviro.2020.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  HammondJ.QiuW.MarkerD.ChamberlainJ.Greaves-TunnellW.BellizziM.et al (2018). HIV Tat causes synapse loss in a mouse model of HIV-associated neurocognitive disorder that is independent of the classical complement cascade component C1q.Glia662563–2574. 10.1002/glia.23511

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  HaralambousE.DollyS.HibberdM.LittD.UdalovaI.O’dwyerC.et al (2006). Factor H, a regulator of complement activity, is a major determinant of meningococcal disease susceptibility in UK Caucasian patients.Scand. J. Infect. Dis.38764–771. 10.1080/00365540600643203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  HartmannK.Sepulveda-FallaD.RoseI.MadoreC.MuthC.MatschkeJ.et al (2019). Complement 3(+)-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia.Acta Neuropathol. Commun.7:83. 10.1186/s40478-019-0735-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  HasebeR.RaymondG.HoriuchiM.CaugheyB. (2012). Reaction of complement factors varies with prion strains in vitro and in vivo.Virology423205–213. 10.1016/j.virol.2011.11.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  HenriquezS.BrettR.AlexanderJ.PrattJ.RobertsC. (2009). Neuropsychiatric disease and Toxoplasma gondii infection.Neuroimmunomodulation16122–133. 10.1159/000180267

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  HillJ.ZhaoY.ClementC.NeumannD.LukiwW. (2009). HSV-1 infection of human brain cells induces miRNA-146a and Alzheimer-type inflammatory signaling.Neuroreport201500–1505. 10.1097/WNR.0b013e3283329c05

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  HongS.Beja-GlasserV.NfonoyimB.FrouinA.LiS.RamakrishnanS.et al (2016). Complement and microglia mediate early synapse loss in Alzheimer mouse models.Science352712–716. 10.1126/science.aad8373

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  HoweD.SibleyL. (1995). Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease.J. Infect. Dis.1721561–1566. 10.1093/infdis/172.6.1561

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  HuangW.WangY.MahmmodY.WangJ.LiuT.ZhengY.et al (2019). A double-edged sword: complement component 3 in Toxoplasma gondii infection.Proteomics19e1800271. 10.1002/pmic.201800271

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  IdroR.MarshK.JohnC.NewtonC. (2010). Europe PMC funders group cerebral malaria?; mechanisms of brain injury and strategies for improved neuro-cognitive outcome.Pediatr. Res.68267–274. 10.1203/00006450-201011001-00524

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  IschenkoA.SayahS.PatteC.AndreevS.GasqueP.SchouftM. T.et al (1998). Expression of a functional anaphylatoxin C3a receptor by astrocytes.J. Neurochem.712487–2496.

  • Google Scholar

• 90

  ItzhakiR. (2018). Corroboration of a Major role for herpes simplex virus type 1 in Alzheimer’s disease.Front. Aging Neurosci.10:324. 10.3389/fnagi.2018.00324

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  IvanovaD.DentonS.FettelK.SondgerothK.Munoz GutierrezJ.BangouraB.et al (2019). Innate lymphoid cells in protection, pathology, and adaptive immunity during apicomplexan infection.Front. Immunol.10:196. 10.3389/fimmu.2019.00196

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  JohanssonL.RytkonenA.BergmanP.AlbigerB.KällströmH.HökfeltT.et al (2003). CD46 in meningococcal disease.Science301373–375. 10.1126/science.1086476

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  JohanssonL.RytkönenA.WanH.BergmanP.PlantL.AgerberthB.et al (2005). Human-like immune responses in CD46 transgenic mice.J. Immunol.175433–440. 10.4049/jimmunol.175.1.433

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  JohnsonU.OhlssonK.OlssonI. (1976). Effects of granulocyte neutral proteases on complement components.Scand. J. Immunol.5421–426. 10.1111/j.1365-3083.1976.tb00296.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  JönssonG.TruedssonL.SturfeltG.OxeliusV.BraconierJ.SjöholmA. (2005). Hereditary C2 deficiency in Sweden: frequent occurrence of invasive infection, atherosclerosis, and rheumatic disease.Medicine8423–34.

  • Google Scholar

• 96

  KaneS.FarleyT.GordonE.EstepJ.BenderH.MorenoJ.et al (2017). Complement regulatory protein factor H Is a soluble prion receptor that potentiates peripheral prion pathogenesis.J. Immunol.1993821–3827. 10.4049/jimmunol.1701100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  KanekoY.TakashimaY.XuaunX.IgarashiI.NagasawaH.MikamiT.et al (2004). Natural IgM antibodies in sera from various animals but not the cat kill Toxoplasma gondii by activating the classical complement pathway.Parasitology128123–129. 10.1017/s0031182003004414

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  KapadiaS.LevineB.SpeckS.VirginH.IV (2002). Critical role of complement and viral evasion of complement in acute, persistent, and latent gamma-herpesvirus infection.Immunity17143–155. 10.1016/s1074-7613(02)00369-2

  • CrossRef
  • Google Scholar

• 99

  KapadiaS.MolinaH.van BerkelV.SpeckS.VirginH.IV (1999). Murine gammaherpesvirus 68 encodes a functional regulator of complement activation.J. Virol.737658–7670. 10.1128/JVI.73.9.7658-7670.1999

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  KennedyA.SchmidtC.ThompsonJ.WeissG.TaechalertpaisarnT.GilsonP.et al (2016). Recruitment of factor H as a novel complement evasion strategy for blood-stage Plasmodium falciparum infection.J. Immunol.1961239–1248. 10.4049/jimmunol.1501581

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  KennedyA.WijeyewickremaL.HugloA.LinC.PikeR.CowmanA.et al (2017). Recruitment of human C1 esterase inhibitor controls complement activation on blood stage Plasmodium falciparum merozoites.J. Immunol.1984728–4737. 10.4049/jimmunol.1700067

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  KimH.ErdmanL.LuZ.SerghidesL.ZhongK.DhabangiA.et al (2014). Functional roles for C5a and C5aR but Not C5L2 in the pathogenesis of human and experimental cerebral malaria.Infect. Immun.82371–379. 10.1128/IAI.01246-13

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  KingB.RenströmE.BlomA. (2019). Intracellular cytosolic complement component C3 regulates cytoprotective autophagy in pancreatic beta cells by interaction with ATG16L1.Autophagy15919–921. 10.1080/15548627.2019.1580515

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  KleinM.KaeserP.SchwarzP.WeydH.XenariosI.ZinkernagelR.et al (2001). Complement facilitates early prion pathogenesis.Nat. Med.7488–492. 10.1038/86567

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  KoelmanD.BrouwerM.van de BeekD. (2019). Targeting the complement system in bacterial meningitis.Brain1423325–3337. 10.1093/brain/awz222

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  KolevM.RusevaM.HarrisC.MorganB.DonevR. (2009). Implication of complement system and its regulators in Alzheimer’s disease.Curr. Neuropharmacol.71–8. 10.2174/157015909787602805

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  KongD.ChenZ.WangJ.LvQ.JiangH.ZhengY.et al (2017). Interaction of factor H-binding protein of Streptococcus suis with globotriaosylceramide promotes the development of meningitis.Virulence81290–1302. 10.1080/21505594.2017.1317426

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  KovacsG.GasqueP.StröbelT.Lindeck-PozzaE.StrohschneiderM.IronsideJ.et al (2004). Complement activation in human prion disease.Neurobiol. Dis.1521–28. 10.1016/j.nbd.2003.09.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  KraiczyP.SkerkaC.KirschfinkM.BradeV.ZipfelP. (2001). Immune evasion of Borrelia burgdorferi by acquisition of human complement regulators FHL-1/reconectin and Factor H.Eur. J. Immunol.311674–1684. 10.1002/1521-4141(200106)31:6<1674::aid-immu1674<3.0.co;2-2

  • CrossRef
  • Google Scholar

• 110

  KulkarniH.ElvingtonM.PerngY.LiszewskiM.ByersD.FarkouhC.et al (2019). Intracellular C3 protects human airway epithelial cells from stress-associated cell death.Am. J. Respir. Cell Mol. Biol.60144–157. 10.1165/rcmb.2017-0405OC

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  KumarM.VarunC.DeyG.RavikumarR.MahadevanA.ShankarS.et al (2018). Identification of host-response in cerebral malaria patients using quantitative proteomic analysis.Proteomics Clin. Appl.12:e1600187. 10.1002/prca.201600187

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  KwonH.KohS. (2020). Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes.Transl. Neurodegener.9:42. 10.1186/s40035-020-00221-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  LacknerP.HametnerC.BeerR.BurgerC.BroessnerG.HelbokR.et al (2008). Complement factors C1q, C3 and C5 in brain and serum of mice with cerebral malaria.Malar. J.7:207. 10.1186/1475-2875-7-207

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  LalliP.StrainicM.YangM.LinF.MedofM.HeegerP. (2008). Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis.Blood1121759–1766. 10.1182/blood-2008-04-151068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  LandlingerC.OberleitnerL.GruberP.NoigesB.YatsykK.SanticR.et al (2015). Active immunization against complement factor C5a: a new therapeutic approach for Alzheimer’s disease.J. Neuroinflammation12:50. 10.1186/s12974-015-0369-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  LengF.EdisonP. (2020). Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?Nat. Rev. Neurol.17157–172. 10.1038/s41582-020-00435-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  LiY.SeveranceE.ViscidiR.YolkenR.XiaoJ. (2019). Persistent Toxoplasma infection of the brain induced neurodegeneration associated with activation of complement and microglia.Infect. Immun.87:e00139-19. 10.1128/IAI.00139-19

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  LibbeyJ.CusickM.DotyD.FujinamiR. (2017). Complement components are expressed by infiltrating macrophages/activated microglia early following viral infection.Viral Immunol.30304–314. 10.1089/vim.2016.0175

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  LionakisM.LimJ.LeeC.MurphyP. (2011). Organ-specific innate immune responses in a mouse model of invasive candidiasis.J. Innate Immun.3180–199. 10.1159/000321157

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  LiszewskiM.ElvingtonM.KulkarniH.AtkinsonJ. (2017). Complement’s hidden arsenal: New insights and novel functions inside the cell.Mol. Immunol.842–9. 10.1016/j.molimm.2017.01.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  LiszewskiM.FarriesT.LublinD.RooneyI.AtkinsonJ. (1996). Control of the complement system.Adv. Immunol.61201–283. 10.1016/s0065-2776(08)60868-8

  • CrossRef
  • Google Scholar

• 122

  LiszewskiM.KolevM.Le FriecG.LeungM.BertramP.FaraA.et al (2013). Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.Immunity391143–1157. 10.1016/j.immuni.2013.10.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  LiszewskiM.LeungM.CuiW.SubramanianV.ParkinsonJ.BarlowP.et al (2000). Dissecting sites important for complement regulatory activity in membrane cofactor protein (MCP; CD46).J. Biol. Chem.27537692–37701. 10.1074/jbc.M004650200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  LiuF.DaiS.GordonJ.QinX. (2014). Complement and HIV-I infection/HIV-associated neurocognitive disorders.J. Neurovirol.20184–198. 10.1007/s13365-014-0243-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  LovchikJ.LipscombM. (1993). Role for C5 and neutrophils in the pulmonary intravascular clearance of circulating Cryptococcus neoformans.Am. J. Respir. Cell Mol. Biol.9617–627. 10.1165/ajrcmb/9.6.617

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  LvY.ChenC.ZhangB.XiaoK.WangJ.ChenL.et al (2014). Remarkable activation of the complement system and aberrant neuronal localization of the membrane attack complex in the brain tissues of scrapie-infected rodents.Mol. Neurobiol.521165–1179. 10.1007/s12035-014-8915-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  LyzogubovV.WuX.JhaP.TytarenkoR.TriebwasserM.KolarG.et al (2014). Complement regulatory protein CD46 protects against choroidal neovascularization in mice.Am. J. Pathol.1842537–2548. 10.1016/j.ajpath.2014.06.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  MahmoudM. E.FereigR.NishikawaY. (2017). Involvement of host defense mechanisms against Toxoplasma gondii infection in anhedonic and despair-like behaviors in mice.Infect. Immun.85:e00007-17.

  • Google Scholar

• 129

  ManchesterM.EtoD.OldstoneM. (1999). Characterization of the inflammatory response during acute measles encephalitis in NSE-CD46 transgenic mice.J. Neuroimmunol.96207–217. 10.1016/s0165-5728(99)00036-3

  • CrossRef
  • Google Scholar

• 130

  MarkiewskiM. M.LambrisJ. D. (2007). The role of complement in inflammatory diseases from behind the scenes into the spotlight.Am. J. Pathol.171715–727. 10.2353/ajpath.2007.070166

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  MarraC. (2018). Central nervous system infection with Toxoplasma gondii.Handb. Clin. Neurol.152117–122. 10.1016/B978-0-444-63849-6.00009-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  MathernD.HeegerP. (2015). Molecules great and small: the complement system.Clin. J. Am. Soc. Nephrol.101636–1650. 10.2215/CJN.06230614

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  MatsuoK.ShindoA.NiwaA.TabeiK.AkatsuH.HashizumeY.et al (2017). Complement activation in capillary cerebral amyloid angiopathy.Dement. Geriatr. Cogn. Disord.44343–353.

  • Google Scholar

• 134

  MatsushitaM.FujitaT. (1995). Cleavage of the third component of complement (C3) by mannose-binding protein-associated serine protease (MASP) with subsequent complement activation.Immunobiology194443–448. 10.1016/S0171-2985(11)80110-5

  • CrossRef
  • Google Scholar

• 135

  MauryA.LyoubiA.Peiffer-SmadjaN.de BrouckerT.MeppielE. (2021). Neurological manifestations associated with SARS-CoV-2 and other coronaviruses: a narrative review for clinicians.Rev. Neurol.17751–64. 10.1016/j.neurol.2020.10.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  McChesneyM.OldstoneM. (1989). Virus-induced immunosuppression: infections with measles virus and human immunodeficiency virus.Adv. Immunol.45335–380. 10.1016/s0065-2776(08)60696-3

  • CrossRef
  • Google Scholar

• 137

  McDonaldC.CahillL.HoK.YangJ.KimH.SilverK.et al (2015). Experimental malaria in pregnancy induces neurocognitive injury in uninfected offspring via a C5a-C5a receptor dependent pathway.PLoS Pathog.11:e1005140. 10.1371/journal.ppat.1005140

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  McDonaldC.ElphinstoneR.KainK. (2013). The impact of placental malaria on neurodevelopment of exposed infants: a role for the complement system?Trends Parasitol.29213–219. 10.1016/j.pt.2013.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  McGovernG.JeffreyM. (2007). Scrapie-specific pathology of sheep lymphoid tissues.PLoS One.2:e1304. 10.1371/journal.pone.0001304

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  McGuireJ.GillA.DouglasS.KolsonD., and CNS HIV Antiretroviral Therapy Effects Research (Charter) Group (2016). The complement system, neuronal injury, and cognitive function in horizontally-acquired HIV-infected youth.J. Neurovirol.22823–830. 10.1007/s13365-016-0460-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  McQuaidS.CosbyS. (2002). An immunohistochemical study of the distribution of the measles virus receptors, CD46 and SLAM, in normal human tissues and subacute sclerosing panencephalitis.Lab. Invest.82403–409. 10.1038/labinvest.3780434

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  MécharlesS.HerrmannC.PoullainP.TranT.DeschampsN.MathonG.et al (2016). Acute myelitis due to Zika virus infection.Lancet387:1481. 10.1016/S0140-6736(16)00644-9

  • CrossRef
  • Google Scholar

• 143

  MehlhopE.WhitbyK.OliphantT.MarriA.EngleM.DiamondM. (2005). Complement activation is required for induction of a protective antibody response against West Nile virus infection.J. Virol.797466–7477. 10.1128/JVI.79.12.7466-7477.2005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  Mook-KanamoriB.GeldhoffM.van der PollT.van de BeekD. (2011). Pathogenesis and pathophysiology of pneumococcal meningitis.Clin. Microbiol. Rev.24557–591. 10.1128/CMR.00008-11

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  MorganB. (2015). The role of complement in neurological and neuropsychiatric diseases.Expert Rev. Clin. Immunol.111109–1119. 10.1586/1744666X.2015.1074039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  MorganB. (2018). Complement in the pathogenesis of Alzheimer’s disease.Semin. Immunopathol.40113–124. 10.1007/s00281-017-0662-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  MukT.StensballeA.PankratovaS.NguyenD.BrunseA.SangildP.et al (2019). Rapid Proteome changes in plasma and cerebrospinal fluid following bacterial infection in preterm newborn pigs.Front. Immunol.10:2651. 10.3389/fimmu.2019.02651

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  NatafS.StahelP.DavoustN.BarnumS. (1999). Complement anaphylatoxin receptors on neurons: new tricks for old receptors?Trends Neurosci.22397–402. 10.1016/s0166-2236(98)01390-3

  • CrossRef
  • Google Scholar

• 149

  NorrisG.SmirnovI.FilianoA.ShadowenH.CodyK.ThompsonJ.et al (2018). Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury.J. Exp. Med.2151789–1801. 10.1084/jem.20172244

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  OgataA.CzubS.OgataS.CosbyS.McQuaidS.BudkaH.et al (1997). Absence of measles virus receptor (CD46) in lesions of subacute sclerosing panencephalitis brains.Acta Neuropathol.94444–449. 10.1007/s004010050731

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  ÓlafssonE.BarraganA. (2020). The unicellular eukaryotic parasite Toxoplasma gondii hijacks the migration machinery of mononuclear phagocytes to promote its dissemination.Biol. Cell112239–250. 10.1111/boc.202000005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  OldstoneM.LewickiH.ThomasD.TishonA.DalesS.PattersonJ.et al (1999). Measles virus infection in a transgenic model: virus-induced immunosuppression and central nervous system disease.Cell98629–640. 10.1016/s0092-8674(00)80050-1

  • CrossRef
  • Google Scholar

• 153

  OlivierI.CacabelosR.NaidooV. (2018). Risk factors and pathogenesis of HIV-associated neurocognitive disorder: the role of host genetics.Int. J. Mol. Sci.19:3594. 10.3390/ijms19113594

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  OSullivanJ.PrestonR.OReganN.ODonnellJ. (2016). Emerging roles for hemostatic dysfunction in malaria pathogenesis.Blood1272281–2288. 10.1182/blood-2015-11-636464

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  PaisT.Penha-GonçalvesC. (2019). Brain endothelium: the “innate immunity response hypothesis” in cerebral malaria pathogenesis.Front. Immunol.9:3100. 10.3389/fimmu.2018.03100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  PanackalA.WilliamsonP. (2015). Fungal infections of the central nervous system.Continuum (Minneap. Minn)211662–1678. 10.1212/CON.0000000000000241

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  PasupuletiM.WalseB.NordahlE.MörgelinM.MalmstenM.SchmidtchenA. (2007). Preservation of antimicrobial properties of complement peptide C3a, from invertebrates to humans.J. Biol. Chem.2822520–2528. 10.1074/jbc.M607848200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  PatelS.BerghoutJ.LovegroveF.AyiK.ConroyA.SerghidesL.et al (2008). C5 deficiency and C5a or C5aR blockade protects against cerebral malaria.J. Exp. Med.2051133–1143. 10.1084/jem.20072248

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  Perez-AlcazarM.DaborgJ.StokowskaA.WaslingP.BjörefeldtA.KalmM.et al (2014). Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3.Exp Neurol.253154–164. 10.1016/j.expneurol.2013.12.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  PerlmutterD.ColtenH. (1986). Molecular immunobiology of complement biosynthesis: a model of single-cell control of effector-inhibitor balance.Annu. Rev. Immunol.4231–251. 10.1146/annurev.iy.04.040186.001311

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  PianY.GanS.WangS.GuoJ.WangP.ZhengY.et al (2012). Fhb, a novel factor H-binding surface protein, contributes to the antiphagocytic ability and virulence of Streptococcus suis.Infect. Immun.802402–2413. 10.1128/IAI.06294-11

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  PittmanK.KnollL. (2015). Long-Term relationships: the complicated interplay between the host and the developmental stages of Toxoplasma gondii during acute and chronic infections.Microbiol. Mol. Biol. Rev.79387–401. 10.1128/MMBR.00027-15

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  PomaresC.DevillardS.HolmesT.OlariuT.PressC.RamirezR.et al (2018). Genetic characterization of Toxoplasma gondii DNA samples isolated from humans living in North America: an unexpected high prevalence of atypical genotypes.J. Infect. Dis.2181783–1791. 10.1093/infdis/jiy375

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  Pozo-RodrigálvarezA.OllarantaR.SkoogJ.PeknyM.PeknaM. (2021). Hyperactive behavior and altered brain morphology in adult complement C3a receptor deficient mice.Front. Immunol.12:604812. 10.3389/fimmu.2021.604812

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  PrusinerS. (1998). Prions.Proc. Natl. Acad. Sci. U.S.A.9513363–13383. 10.1073/pnas.95.23.13363

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  PrusinerS.ScottM.DeArmondS.CohenF. (1998). Prion protein biology.Cell93337–348. 10.1016/s0092-8674(00)81163-0

  • CrossRef
  • Google Scholar

• 167

  RahpeymaiY.HietalaM. A.WilhelmssonU.FotheringhamA.DaviesI.NilssonA. K.et al (2006). Complement: a novel factor in basal and ischemia-induced neurogenesis.EMBO J.251364–1374.

  • Google Scholar

• 168

  RajasinghamR.SmithR.ParkB.JarvisJ.GovenderN.ChillerT.et al (2017). Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis.Lancet Infect. Dis.17873–881. 10.1016/S1473-3099(17)30243-8

  • CrossRef
  • Google Scholar

• 169

  RallG.ManchesterM.DanielsL.CallahanE.BelmanA.OldstoneM. (1997). A transgenic mouse model for measles virus infection of the brain.Proc. Natl. Acad. Sci. U.S.A.944659–4663. 10.1073/pnas.94.9.4659

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  RambachG.MaierH.VagoG.MohsenipourI.Lass-FlörlC.DefantA.et al (2008). Complement induction and complement evasion in patients with cerebral aspergillosis.Microbes Infect.101567–1576. 10.1016/j.micinf.2008.09.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  RamosT.DarleyM.HuX.BillkerO.RaynerJ.AhrasM.et al (2011). Cutting edge: the membrane attack complex of complement is required for the development of murine experimental cerebral malaria.J. Immunol.1866657–6660. 10.4049/jimmunol.1100603

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  RamosT.DarleyM.WeckbachS.StahelP.TomlinsonS.BarnumS. (2012). The C5 convertase is not required for activation of the terminal complement pathway in murine experimental cerebral malaria.J. Biol Chem.28724734–24738. 10.1074/jbc.C112.378364

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  RasmussenS.JamiesonD.HoneinM.PetersenL. (2016). Zika virus and birth defects–reviewing the evidence for causality.N. Engl. J. Med.3741981–1987. 10.1056/NEJMsr1604338

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  ReadheadB.Haure-MirandeJ.FunkC.RichardsM.ShannonP.HaroutunianV.et al (2018). Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus.Neuron9964–82.e7. 10.1016/j.neuron.2018.05.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  RiggleB.MillerL.PierceS. (2020). Desperately seeking therapies for cerebral malaria.J. Immunol.204327–334. 10.4049/jimmunol.1900829

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  RobakisN. (2020). What do recent clinical trials teach us about the etiology of AD.Adv. Exp. Med. Biol.1195:167. 10.1007/978-3-030-32633-3_23

  • CrossRef
  • Google Scholar

• 177

  RogersJ.CooperN.WebsterS.SchultzJ.McGeerP.StyrenS.et al (1992). Complement activation by beta-amyloid in Alzheimer disease.Proc. Natl. Acad. Sci. U.S.A.8910016–10020. 10.1073/pnas.89.21.10016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  RosaT.FlammersfeldA.NgwaC.KiesowR.FischerP.ZipfelP.et al (2016). The Plasmodium falciparum blood stages acquire factor H family proteins to evade destruction by human complemen.Cell. Microbiol.18573–590. 10.1111/cmi.12535

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  RossS.DensenP. (1984). Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency.Medicine63243–273.

  • Google Scholar

• 180

  RostagnoA.ReveszT.LashleyT.TomidokoroY.MagnottiL.BraendgaardH.et al (2002). Complement activation in chromosome 13 dementias. Similarities with Alzheimer’s disease.J. Biol. Chem.27749782–49790. 10.1074/jbc.M206448200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  RoweJ.MouldsJ.NewboldC.MillerL. (1997). P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1.Nature388292–295. 10.1038/40888

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  Rubio-PerezJ.Morillas-RuizJ. (2012). A review: inflammatory process in Alzheimer’s disease, role of cytokines.ScientificWorldJournal2012:756357. 10.1100/2012/756357

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  RuhnkeM.KoflaG.OttoK.SchwartzS. (2007). CNS aspergillosis: recognition, diagnosis and management.CNS Drugs21659–676. 10.2165/00023210-200721080-00004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  RussoF.JungmannP.Beltrão-BragaP. (2017). Zika infection and the development of neurological defects.Cell Microbiol.19:e12744. 10.1111/cmi.12744

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  RussoJ.BohenzkyR.ChienM.ChenJ.YanM.MaddalenaD.et al (1996). Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8).Proc. Natl. Acad. Sci. U.S.A.9314862–14867. 10.1073/pnas.93.25.14862

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  SadekJ.PergamS.HarringtonJ.EchevarriaL.DavisL.GoadeD.et al (2010). Persistent neuropsychological impairment associated with West Nile virus infection.J. Clin. Exp. Neuropsychol.3281–87. 10.1080/13803390902881918

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  SaidJ.TasakaT.de VosS.KoefflerH. (1997). Kaposi’s sarcoma-associated herpesvirus/human herpesvirus type 8 encephalitis in HIV-positive and -negative individuals.AIDS111119–1122. 10.1097/00002030-199709000-00006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  SasaiM.PradiptaA.YamamotoM. (2018). Host immune responses to Toxoplasma gondii.Int. Immunol.30113–119.

  • Google Scholar

• 189

  SaulA.LashleyT.ReveszT.HoltonJ.GhisoJ.CoomaraswamyJ.et al (2013). Abundant pyroglutamate-modified ABri and ADan peptides in extracellular and vascular amyloid deposits in familial British and Danish dementias.Neurobiol. Aging341416–1425. 10.1016/j.neurobiolaging.2012.11.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  SchaferD.LehrmanE.KautzmanA.KoyamaR.MardinlyA.YamasakiR.et al (2012). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.Neuron74691–705. 10.1016/j.neuron.2012.03.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  SchartzN.TennerA. (2020). The good, the bad, and the opportunities of the complement system in neurodegenerative disease.J. Neuroinflammation17:354. 10.1186/s12974-020-02024-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  SchmidtC.KennedyA.ThamW. (2015). More than just immune evasion: hijacking complement by Plasmodium falciparum.Mol. Immunol.6771–84. 10.1016/j.molimm.2015.03.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  SchmutzhardE.GerstenbrandF. (1984). Cerebral malaria in Tanzania. Its epidemiology, clinical symptoms and neurological long term sequelae in the light of 66 cases.Trans R. Soc. Trop. Med. Hyg.78351–353. 10.1016/0035-9203(84)90118-4

  • CrossRef
  • Google Scholar

• 194

  SchneiderM.ProsserB.CaesarJ.KugelbergE.LiS.ZhangQ.et al (2009). Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates.Nature458890–893. 10.1038/nature07769

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  SchreiberR.FeldmanH. (1980). Identification of the activator system for antibody to Toxoplasma as the classical complement pathway.J. Infect. Dis.141366–369. 10.1093/infdis/141.3.366

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  SejvarJ.HaddadM.TierneyB.CampbellG.MarfinA.Van GerpenJ.et al (2003). Neurologic manifestations and outcome of West Nile virus infection.JAMA290511–515. 10.1001/jama.290.4.511

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  SekarA.BialasA.de RiveraH.DavisA.HammondT.KamitakiN.et al (2016). Schizophrenia risk from complex variation of complement component 4.Nature530177–183. 10.1038/nature16549

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  SerafiniB.RosicarelliB.FranciottaD.MagliozziR.ReynoldsR.CinqueP.et al (2007). Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain.J. Exp. Med.2042899–2912.

  • Google Scholar

• 199

  ShiQ.ChowdhuryS.MaR.LeK.HongS.CaldaroneB.et al (2017). Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice.Sci. Transl. Med.9:eaaf6295. 10.1126/scitranslmed.aaf6295

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  ShiQ.ColodnerK.MatousekS.MerryK.HongS.KenisonJ.et al (2015). Complement C3-deficient mice fail to display age-related hippocampal decline.J. Neurosci.3513029–13042. 10.1523/JNEUROSCI.1698-15.2015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  ShinjyoN.HikosakaK.KidoY.YoshidaH.NoroseK. (2021). Toxoplasma infection induces sustained up-regulation of complement factor B and C5a receptor in the mouse brain via microglial activation: implication for the alternative complement pathway activation and anaphylatoxin signaling in cerebral toxoplasmosis.Front. Immunol.11:603924. 10.3389/fimmu.2020.603924

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  ShinjyoN.StahlbergA.DragunowM.PeknyM.PeknaM. (2009). Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells in vitro.Stem Cells272824–2832. 10.1002/stem.225

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  SikorskiP.CommodaroA.GriggM. (2020). Toxoplasma gondii recruits factor H and C4b-Binding protein to mediate resistance to serum killing and promote parasite persistence in vivo.Front. Immunol.10:3105. 10.3389/fimmu.2019.03105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  SilamutK.PhuN.WhittyC.TurnerG.LouwrierK.MaiN.et al (1999). A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain.Am. J. Pathol.155395–410. 10.1016/S0002-9440(10)65136-X

  • CrossRef
  • Google Scholar

• 205

  Silva-BarriosS.StägerS. (2017). Protozoan parasites and type I IFNs.Front. Immunol.8:14. 10.3389/fimmu.2017.00014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  SinghG.AngwaforS.NjamnshiA.FraimowH.SanderJ. (2020). Zoonotic and vector-borne parasites and epilepsy in low-income and middle-income countries.Nat. Rev. Neurol.16333–345. 10.1038/s41582-020-0361-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  SkaperS. (2012). Alzheimer’s disease and amyloid: culprit or coincidence?Int. Rev. Neurobiol.102277–316. 10.1016/B978-0-12-386986-9.00011-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  SouzaI.Barros-AragãoF.FrostP.FigueiredoC.ClarkeJ. (2019). Late neurological consequences of Zika Virus infection: risk factors and pharmaceutical approaches.Pharmaceuticals12:60. 10.3390/ph12020060

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  SpadaforaC.AwandareG.KopydlowskiK.CzegeJ.MochJ.FinbergR.et al (2010). Complement receptor 1 is a sialic acid-independent erythrocyte receptor of Plasmodium falciparum.PLoS Pathog.6:e1000968. 10.1371/journal.ppat.1000968

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  SpethC.DierichM.GasqueP. (2002). Neuroinvasion by pathogens: a key role of the complement system.Mol. Immunol.38669–679. 10.1016/s0161-5890(01)00104-3

  • CrossRef
  • Google Scholar

• 211

  SpethC.WilliamsK.HagleitnerM.WestmorelandS.RambachG.MohsenipourI.et al (2004). Complement synthesis and activation in the brain of SIV-infected monkeys.J. Neuroimmunol.15145–54. 10.1016/j.jneuroim.2004.02.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  SprongT.RoosD.WeemaesD.NeelemanC.GeesingC.MollnesT.et al (2006). Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections.Blood1074865–4870. 10.1182/blood-2005-07-2820

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  StahelP.FreiK.FontanaA.EugsterH.AultB.BarnumS. (1997). Evidence for intrathecal synthesis of alternative pathway complement activation proteins in experimental meningitis.Am. J. Pathol.151897–904.

  • Google Scholar

• 214

  StepanovaE.KondrashinA.SergievV.MorozovaL.TurbabinaN.MaksimovaM.et al (2019). Toxoplasmosis and mental disorders in the Russian Federation (with special reference to schizophrenia).PLoS One14:e0219454. 10.1371/journal.pone.0219454

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  StevensB.AllenN. J.VazquezL. E.HowellG. R.ChristophersonK. S.NouriN.et al (2007). The classical complement cascade mediates CNS synapse elimination.Cell1311164–1178. 10.1016/j.cell.2007.10.036

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  StokowskaA.AtkinsA.MoránJ.PeknyT.BulmerL.PascoeM.et al (2017). Complement peptide C3a stimulates neural plasticity after experimental brain ischemia.Brain140353–369. 10.1093/brain/aww314

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  StokowskaA.PeknaM. (2018). “Complement C3a: shaping the plasticity of the post-stroke brain,” in Cellular and Molecular Approaches to Regeneration and Repair. Springer Series in Translational Stroke Research, edsLapchakP.ZhangJ. (Cham: Springer), 521–541. 10.1007/978-3-319-66679-2_26

  • CrossRef
  • Google Scholar

• 218

  StorchM.PiddlesdenS.HaltiaM.IivanainenM.MorganP.LassmannH. (1998). Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination.Ann. Neurol.43465–471. 10.1002/ana.410430409

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  StracciariA.BottiniG.GuarinoM.MagniE.PantoniL., and “Cognitive and Behavioral Neurology” Study Group of the Italian Neurological Society (2021). Cognitive and behavioral manifestations in SARS-CoV-2 infection: not specific or distinctive features?Neurol Sci.422273–2281. 10.1007/s10072-021-05231-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  SunD.ZhangM.LiuG.WuH.LiC.ZhouH.et al (2016). Intravascular clearance of disseminating Cryptococcus neoformans in the brain can be improved by enhancing neutrophil recruitment in mice.Eur. J. Immunol.461704–1714. 10.1002/eji.201546239

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  TaniguchiY.Appiah-KwartengC.MurakamiM.FukumotoJ.NagamuneK.MatsuoT.et al (2018). Atypical virulence in a type III Toxoplasma gondii strain isolated in Japan.Parasitol. Int.67587–592.

  • Google Scholar

• 222

  TennerA. (2020). Complement-mediated events in Alzheimer’s disease: mechanisms and potential therapeutic targets.J. Immunol.204306–315. 10.4049/jimmunol.1901068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  TennerA.StevensB.WoodruffT. (2018). New tricks for an ancient system: physiological and pathological roles of complement in the CNS.Mol. Immunol.1023–13. 10.1016/j.molimm.2018.06.264

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  ThamW.WilsonD.LopatickiS.SchmidtC.Tetteh-QuarcooP.BarlowP.et al (2010). Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand.Proc. Natl. Acad. Sci. U.S.A.10717327–17332. 10.1073/pnas.1008151107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  TsoF.SawyerA.KwonE.MudendaV.LangfordD.ZhouY.et al (2017). Kaposi’s sarcoma-associated herpesvirus infection of neurons in HIV-positive patients.J. Infect. Dis.2151898–1907. 10.1093/infdis/jiw545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  TuiteA.EliasM.PicardS.MullickA.GrosP. (2005). Genetic control of susceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice.Genes Immun.6672–682. 10.1038/sj.gene.6364254

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  TyebjiS.SeizovaS.GarnhamA.HannanA.TonkinC. (2019a). Impaired social behaviour and molecular mediators of associated neural circuits during chronic Toxoplasma gondii infection in female mice.Brain Behav. Immun.8088–108. 10.1016/j.bbi.2019.02.028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  TyebjiS.SeizovaS.HannanA.TonkinC. (2019b). Toxoplasmosis: a pathway to neuropsychiatric disorder.Neurosci. Biobehav. Rev.9672–92. 10.1016/j.neubiorev.2018.11.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  van de BeekD.BrouwerM.HasbunR.KoedelU.WhitneyC.WijdicksE. (2016). Community-acquired bacterial meningitis.Nat. Rev. Dis. Primers2:16074. 10.1038/nrdp.2016.74

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  van de BeekD.de GansJ.SpanjaardL.WeisfeltM.ReitsmaJ.VermeulenM. (2004). Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series.N. Engl. J. Med.3511849–1859. 10.1056/NEJMoa040845

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  Van der HeydeH.NolanJ.CombesV.GramagliaI.GrauG. (2006). A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction.Trends Parasitol.22503–508. 10.1016/j.pt.2006.09.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  VasekM.GarberC.DorseyD.DurrantD.BollmanB.SoungA.et al (2016). A complement-microglial axis drives synapse loss during virus-induced memory impairment.Nature534538–543. 10.1038/nature18283

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  VeerhuisR.NielsenH.TennerA. (2011). Complement in the brain.Mol. Immunol.481592–1603. 10.1016/j.molimm.2011.04.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  VillegasM.SciuttoE.RosettiM.FleuryA.FragosoG. (2019). Association of TRAF1/C5 locus polymorphisms with epilepsy and clinical traits in mexican patients with neurocysticercosis.Infect Immun.87e347–e319. 10.1128/IAI.00347-19

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  VirginH.IVLatreilleP.WamsleyP.HallsworthK.WeckK.Dal CantoA.et al (1997). Complete sequence and genomic analysis of murine gammaherpesvirus 68.J. Virol.715894–5904. 10.1128/JVI.71.8.5894-5904.1997

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 236

  WassmerS.de SouzaJ.FrèreC.CandalF.Juhan-VagueI.GrauG. (2006). TGF-beta1 released from activated platelets can induce TNF-stimulated human brain endothelium apoptosis: a new mechanism for microvascular lesion during cerebral malaria.J. Immunol.1761180–1184. 10.4049/jimmunol.176.2.1180

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  WassmerS.GrauG. (2017). Severe malaria: what’s new on the pathogenesis front?Int. J. Parasitol.47145–152. 10.1016/j.ijpara.2016.08.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  WeaverS.BarrettA. (2004). Transmission cycles, host range, evolution and emergence of arboviral disease.Nat. Rev. Microbiol.2789–801. 10.1038/nrmicro1006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  WeaverS.FerroC.BarreraR.BoshellJ.NavarroJ. (2004). Venezuelan equine encephalitis.Annu. Rev. Entomol.49141–174. 10.1146/annurev.ento.49.061802.123422

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  WHO (2019). Dementia Fact sheet.Geneva: WHO.

  • Google Scholar

• 241

  WoehrlB.BrouwerM.MurrC.HeckenbergS.BaasF.PfisterH.et al (2011). Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis.J. Clin. Invest.1213943–3953. 10.1172/JCI57522

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  WoodruffT. M.AgerR. R.TennerA. J.NoakesP. G.TaylorS. M. (2010). The role of the complement system and the activation fragment C5a in the central nervous system.Neuromolecular Med.12179–192.

  • Google Scholar

• 243

  WoollardS.BhargavanB.YuF.KanmogneG. (2014). Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02_AG on human brain microvascular endothelial cells: implications for blood-brain barrier dysfunction.J. Cereb. Blood Flow Metab.341047–1059. 10.1038/jcbfm.2014.54

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  WuK.ZhangT.ZhaoG.MaN.ZhaoS.WangN.et al (2019). The C3a/C3aR axis mediates anti-inflammatory activity and protects against uropathogenic E coli-induced kidney injury in mice.Kidney Int.96612–627. 10.1016/j.kint.2019.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  WuM.BrennanF.LynchJ.MantovaniS.PhippsS.WetselR.et al (2013). The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization.Proc. Natl. Acad. Sci. U.S.A.1109439–9444. 10.1073/pnas.1218815110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  Wyss-CorayT.YanF.LinA.LambrisJ.AlexanderJ.QuiggR.et al (2002). Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice.Proc. Natl. Acad. Sci. U.S.A.9910837–10842. 10.1073/pnas.162350199

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  XiaoJ.LiY.GressittK.HeH.KannanG.SchultzT.et al (2016). Cerebral complement C1q activation in chronic Toxoplasma infection.Brain Behav. Immun.5852–56. 10.1016/j.bbi.2016.04.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  YanamadalaV.FriedlanderR. (2010). Complement in neuroprotection and neurodegeneration.Trends Mol. Med.1669–76. 10.1016/j.molmed.2009.12.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  YuanX.ShanM.YouR.FrazierM. V.HongM. J.WetselR. A.et al (2015). Activation of C3a receptor is required in cigarette smoke-mediated emphysema.Mucosal Immunol.8874–885. 10.1038/mi.2014.118

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  YusufF.HafizM.ShoaibM.AhmedS. (2017). Cerebral malaria: insight into pathogenesis, complications and molecular biomarkers.Infect. Drug Resist.1057–59. 10.2147/IDR.S125436

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  ZhangJ.MalikA.ChoiH.KoR.Dissing-OlesenL.MacVicarB. (2014). Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase.Neuron82195–207. 10.1016/j.neuron.2014.01.043

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  ZwijnenburgP.van der PollT.FlorquinS.PolflietM.van den BergT.DijkstraC.et al (2007). C1 inhibitor treatment improves host defense in pneumococcal meningitis in rats and mice.J. Infect. Dis.196115–123. 10.1086/518609

  • Pubmed Abstract
  • CrossRef
  • Google Scholar