Abstract
Haematophagous arthropods can harbor various pathogens including viruses, bacteria, protozoa, and nematodes. Insects possess an innate immune system comprising of both cellular and humoral components to fight against various infections. Haemocytes, the cellular components of haemolymph, are central to the insect immune system as their primary functions include phagocytosis, encapsulation, coagulation, detoxification, and storage and distribution of nutritive materials. Plasmatocytes and granulocytes are also involved in cellular defense responses. Blood-feeding arthropods, such as mosquitoes and ticks, can harbour a variety of viral pathogens that can cause infectious diseases in both human and animal hosts. Therefore, it is imperative to study the virus-vector-host relationships since arthropod vectors are important constituents of the ecosystem. Regardless of the complex immune response of these arthropod vectors, the viruses usually manage to survive and are transmitted to the eventual host. A multidisciplinary approach utilizing novel and strategic interventions is required to control ectoparasite infestations and block vector-borne transmission of viral pathogens to humans and animals. In this review, we discuss the arthropod immune response to viral infections with a primary focus on the innate immune responses of ticks and mosquitoes. We aim to summarize critically the vector immune system and their infection transmission strategies to mammalian hosts to foster debate that could help in developing new therapeutic strategies to protect human and animal hosts against arthropod-borne viral infections.
Introduction
Insecta is the most abundant group of terrestrial animals, both in terms of numbers as well as species (approx. 5.5 million) (1). However, most insect species are not described (1, 2); about 80% of species yet to be identified (2). Insects provide many essential services in the natural ecosystem as pollinators and biological control agents, and help in nutrient recycling and food resources (3). However, many insect species are serious pests of cash crops or staple food crops. In addition, some insects (including mosquitoes, lice, fleas, and bed bugs), and ticks (Acari) serve as vectors transmitting a variety of pathogens (bacteria, viruses, nematodes and protozoa) to humans and animals (4). Among these, mosquito-borne and tick-borne viruses cause some of the most severe diseases with high fatality rates in humans and animals (5–7). In particular vector-borne viruses, including Zika, West Nile fever, Rift Valley fever, dengue, yellow fever, chikungunya, Japanese encephalitis, Crimean-Congo hemorrhagic fever, tick-borne encephalitis and Alkhurma hemorrhagic fever virus, are a continued threat to human and livestock health globally. Due to globalization and climate change, ticks and mosquitoes are occupying new geographic areas expanding the remit of vector-borne diseases.
Insects have an open circulatory system, the blood (haemolymph) mixes with the interstitial fluid and circulates in a body cavity called the haemocoel (8). Haemocytes or blood cells, the cellular components of haemolymph (9), are classified into various cell types such as prohemocytes, plasmatocytes, granulocytes, coagulocytes, oenocytoids, spherulocytes, thrombocytoids, and crystal cells (not all haemocyte types are present in most insects) (10, 11), with their main functions being immune response to pathogens including detoxification, coagulation, encapsulation and phagocytosis; phagocytosis; other cells are involved in carrying and transferring nutritive materials to various organs (12, 13). Viral transmission in insects is dependent on innate immune response (8). In this review, we discuss the innate immunity of arthropod vectors with specific reference to anti-viral immune responses in ticks and mosquitoes.
Insect innate immune system and pathogen clearance mechanisms
Insect antiviral innate immunity has mostly been studied in Drosophila melanogaster (14). The innate immune system of insects acts through cellular and humoral components (15, 16), which together coordinate against bacterial and viral infections. Cellular immune responses include phagocytosis, nodulation, and encapsulation of pathogens by haemocytes (11, 17). However, during humoral response, pattern-recognition receptors (PRRs), which are germline-encoded, recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecules patterns (DAMPs). PAMPs include bacterial lipopolysaccharide (LPS), peptidoglycan, and fungal β-1,3-glucans (15). PRRs bind to the PAMPs and initiate opsonization of pathogens. The activation of downstream signaling induced by PRRs leads to the synthesis and secretion of effector molecules, for example reactive oxygen species (ROS), antimicrobial peptides (AMPs), and components of the phenoloxidase cascade; these effector molecules restrict infections and clear the intruding pathogens (8, 18–20). Blood sucking insects such as mosquitoes acquire various pathogens during blood feeding and their midgut epithelial cells act as the first line of defense and produce ROS and several AMPs. The expression of genes coding for AMPs depends on various signaling pathways such as Toll, Immune Deficiency (IMD), and Janus Kinase and Signal Transducer and Activator of Transcription (JAK/STAT) pathways; activation of these pathways inhibits viral replication (8, 21, 22). PRRs detect microbial invaders and initiate signaling cascades that hinder their proliferation in the host. This leads to engagement of adaptor molecules establishing multi-protein complexes comprised of kinases, transcription factors, and other regulatory molecules (23). Figure 1 shows the complex interplay of insect innate immune responses.
Figure 1
Insect innate immune mechanisms: When the insect’s immune system recognizes pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs), pathogens encounter a complex system of humoral and cellular responses. Humoral responses include the production of antimicrobial peptides (AMPs), reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI), and a complex enzymatic cascade to regulate clotting or melanization. Cellular immune response involves various haemocytes that participate in phagocytosis/nodulation/encapsulation for pathogen clearance from haemolymph. In addition, different immune cells release toxic factors to kill pathogens, i.e. cell-mediated killing (complement components, etc.). These events take place in the haemocoel of the ticks. The series of immune reactions depict innate immunity. Clotting protein is a unique lipoprotein. Hemolymph clotting is induced upon transglutaminase (TGase) release from hemocytes/tissues. Calcium ions play an important role in the cascade leading to coagulation. TGase is involved in the coagulation, disturbing the chemical nature of the target pathogens. Peroxinectin is an opsonin that does attachment, spreads, and induces degranulation. SOD produces H2O2 from which hypohalic acid is released, which is a toxic substance, Prophenoloxidase activating system (proPO system) is an efficient part of the innate immune response. bGBP is a pattern recognition protein known to bind β-1,3, glucan. Masquerade (Mas-) like protein is also a multifunctional innate immune protein, an opsonin-like peroxinectin, capable of doing pathogen binding, inducing degranulation, and pathogen clearance. TGase, transglutaminase; Ca2+, Calcium, SOD, superoxide dismutase; βGBP, glucan with β-1,3 glucan binding protein; Mas-like protein,-- Masquerade- like protein.
Viral replication may be limited by activation of above-mentioned pathways. However, RNA interference (RNAi) is considered the most potent antiviral defense mechanism; it hinders viral replication yielding small RNAs (using viral double-stranded RNA as a template) targeting viral RNA degradation (24). Thus, innate immune system works through various effector mechanisms including phagocytosis, encapsulation, melanization, nodulation, lysis, RNAi, autophagy, and apoptosis.
Phagocytosis of pathogens by haemocytes
Phagocytosis by haemocytes starts when PRRs such as thioester-containing proteins, Nimrod proteins, β-integrins, and peptidoglycan recognition proteins (PGRPs) bind PAMPs (25, 26). For instance, PGRP-LC initiates the phagocytosis of E. coli in D. melanogaster (26). The pathogen is then taken into a membrane-delimited phagosome. The phagosome fuses with a lysosome (phagolysosome), where the pathogen is digested by hydrolytic enzymes such as lysozyme, proteases, lipases, nucleases, and glycosylases (25). There are haemocytes that circulate in the haemolymph (circulating haemocytes) and tissue-resident haemocytes (sessile haemocytes) (13, 27). Insects have morphologically and functionally distinct haemocyte subpopulations. The classification of haemocytes has not been standardized across Insecta (25); however, the majority of haemocytes are phagocytic (25). In Lepidopterans and Hemipterans, the phagocytic haemocytes are granulocytes, whereas in fruit flies, plasmatocytes show phagocytic activities (13, 27). In mosquitoes, circulating and sessile haemocytes initiate phagocytosis within seconds of making contact with the pathogens (25, 27) and can ingest hundreds of bacteria in a short time.
Encapsulation
Encapsulation is the most common type of defense reaction against parasites. Haemocyte-mediated encapsulation occurs in insects when large pathogens enter the haemolymph, for example, the eggs or larvae of parasites, protozoa and nematodes (25). Encapsulation in insects is of two types: cellular and humoral encapsulation. Haemocytes may or may not be involved in the humoral encapsulation that is associated with phenoloxidase; however, the cellular process may occur without melanization (11). In Galleria mellonella, during encapsulation, granulocytes release the adhesion protein, peroxinectin. It is a multifunctional molecule which is not only used for attachment and spreading but it also enhances encapsulation, degranulation, opsonization and peroxidase activity (28). Thus, this adhesion helps plasmatocytes attach to the layer of granulocytes which is then enclosed by several layers of plasmatocytes, followed by additional granulocytes (11, 25). Multiple layers of plasmatocytes surrounding the pathogen produce a capsule of multi-layered overlapping cells to sequester pathogen. In Drosophila, lamellocytes may commonly be observed in capsules; however, in Lepidoptera, both granulocytes and plasmatocytes are commonly observed in capsules (11, 16). In some cases, accompanied by encapsulation, plasmatocytes deposit pigment around the parasite (melanization). These defense responses, either alone or together, successfully kill parasites (29). In mosquitoes, the complement C3-like protein (AgTEP1) induces an immune response against Plasmodium berghei. Parasite death occurs when protein binds to the surface of the parasite and initiatesencapsulation by haemocytes (30).
Melanization
Melanization is an immune effector mechanism that kills pathogens including bacteria, protozoa, and nematodes; it is also involved in wound healing (25). In melanization reaction, tyrosine converts to melanin precursors and then proteins cross-link to form a melanin layer that impounds an attacking pathogen and establishes a dark proteinaceous capsule. This can cause starvation or oxidative damage resulting in the pathogen’s death (31). Furthermore, this process also facilitates clearing of dead microbes. Melanization occurs with the coordination of PRRs, serine proteases, serine protease inhibitors, and enzymes and starts when PRRs (for example β-1,3 glucan, C-type lectins and Gram-negative binding proteins) recognize PAMPs and initiate a serine protease cascade. Phenoloxidase begins the production of melanin by hydroxylation of tyrosine. Many enzymes and PRRs involved in the melanization process are produced by haemocytes, for instance, oenocytoids (which are large and oval cells, their cytoplasm contains agglomerates of microtubules) (32) are the main producers of prophenoloxidase. Prophenoloxidase (ProPO) participates in melanization (25, 33). Therefore, haemocytes play an important role in clearing microbes from the insects’ haemolymph by forming melanotic capsules (29). Recently, the activity of the phenoloxidase/melanization responses was investigated in Drosophila; it was found that injection of Zika virus into wild-type adult flies caused melanin formation at the injection site by increasing phenoloxidase activity in the hemolymph (34).
Nodulation
The nodulation process involves coordinated adherence of haemocytes in order to enclose large clusters of pathogens followed by melanization (25). In the case of bacterial infections, several haemocytes attach to the aggregates of microbes. This helps in the removal of a considerable number of bacteria from insects’ haemolymph through phagocytosis (11). Thus, haemocytes bind together to form a capsule around the pathogen (25) and nodulation is accomplished by the stimulation of prophenoloxidase and mature nodules’ melanization (11).
Lysis
Lysis is immune-based disruption of the cellular membrane to kill the pathogens. This mechanism is difficult to observe because an immune-based reduction in infection intensity leads to pathogen death that is not an easily visible immune phenotype as compared to phagocytosis, encapsulation, nodulation, and melanization where pathogens can be seen inside haemocytes. Factors such as AMPs induce pathogen death through lysis (25). The AMPs include defensin and defensin-like peptides, cecropin and cecropin-like peptides, attacins and gloverins, and lebocins mostly detected in Diptera, Coleoptera and Lepidoptera and act against bacteria and fungi. Immune signaling pathways govern the production of AMPs. For example, in D. melanogaster, activation of the Toll pathway induces the transcription of drosomycin while activation of the Imd pathway induces the transcription of diptericin (35). Lysozymes are also involved in lytic activity. ROS and RNS (reactive nitrogen intermediates) affect lytic activity in the extracellular environment. Furthermore, reactive species are also involved in the antimicrobial response in the haemocoel (35, 36).
RNA interference
RNAi is a process in which RNA molecules inhibit gene expression or translation by neutralizing targeted mRNA molecules; it is considered an ancient gene silencing pathway connected to antiviral defense (37). Small RNA-guided antiviral immunity was first revealed in plants, and subsequently, in fruit flies (D. melanogaster) and round worms (Caenorhabditis elegans) (37). By studying the function of insect genes, RNAi could be used for insect pest management (38). Among various defenses, activation of the RNAi pathway is the key antiviral mechanism in mosquitoes that leads to viral RNA degradation and replication inhibition (8, 39). The production of small RNAs from long viral double-stranded RNA (dsRNA) has a major role in the RNAi pathway and small RNAs include small interfering RNAs (siRNAs), microRNAs (miRNAs), and PIWI-interacting RNAs (piRNAs) (40). In the small interfering RNA (siRNA) pathway, a ribonuclease, Dicer-2 (Dcr2) cleaves the viral double-stranded RNA (dsRNA) to generate viral siRNAs (41). siRNA leads the Argonaute-2 (Ago-2) protein to target viral RNAs to initiate degradation (41). Ago-2 is a slicer protein and slicer activity is crucial for an effective RNAi response. Furthermore, virus replication is negatively controlled by the transcription of Vago, a cysteine-rich polypeptide that is activated by the binding of viral RNA to Dcr2 (42). In mosquitoes, the PIWI-interacting RNA pathway (piRNA) is also used in antiviral response in addition to the siRNA pathway (39, 43). piRNAs are small non-coding RNAs that interact with proteins, for instance, PIWI, Ago-3, and Aubergine (Aub) to form the piRNA-induced silencing complex (piRISC) and regulate RNA silencing (44). However, piRNA biogenesis seems to vary considerably between germline and somatic cells. Virus-derived piRNAs have been shown to be produced in whole Aedes mosquitoes upon infection with chikungunya and dengue virus (43).
Apoptosis
Apoptosis, the programmed cell death, is characterized by distinct morphological features and energy-dependent biochemical mechanisms which is essential for proper development and functioning of the immune system and normal cell turnover (45). A range of cellular anti-viral mechanisms exist in insects, including incompatibility of viruses with hosts, apoptosis, and shutdown of protein synthesis (1). For example, certain species of Lepidoptera respond to viral infections by inducing apoptosis in infected cells (46). There are two major apoptotic pathways: the intrinsic pathway that is mediated by mitochondria, and the extrinsic pathway mediated by death receptors [CD95, TRAIL-R1 (TNF-related apoptosis-inducing ligand-R1) or TRAIL-R2] activated by their natural ligands, the TNF family. The caspases (cysteine aspartyl-specific proteases) activate in both pathways which cleave cellular substrates leading to the biochemical/morphological changes that cause cell death and inflammation. These two pathways may be linked and influenced by the molecules of one another (47). In Drosophila, apoptosis occurs following intrinsic pathway activated by intracellular signals such as shutdown of protein or mRNA production, or DNA damage, and involves the formation of large complexes at the mitochondrial membrane in the case of baculovirus (46).
Autophagy
Autophagy is the process employed for degradation of intracellular materials and elimination of intracellular pathogens such as bacteria and viruses (48–50). Bacteria can be eliminated by autophagy in Drosophila. During this process, peptidoglycan recognition protein LE (PGRP-LE) on haemocytes recognizes the bacterial peptidoglycan and induces LC3/Atg8 proteins targeting autophagy to clear the infection of Listeria monocytogenes (51). Furthermore, autophagy is employed in the immune reaction against Rift Valley fever virus (52).
Coagulation
In case of injury, an insect’s cuticle serves as the first line of defense, providing a physical and chemical barrier. The open circulatory system of arthropods has efficient mechanisms that can prevent haemolymph loss in case of injury and also trap microbes before their entry and spreading in the body cavity/hemocoel. Haemolymph clotting is of significance in the innate immune system, which has been studied in arthropods, crayfish and horseshoe crab. In the lepidopteran species, there are four steps in clotting system (28) First, haemocyte degranulation establishes extracellular aggregates that seal the wound and makes a soft clot. Then, initiation of the prophenoloxidase cascade/tranglutaminase (TGase) facilitates crosslinking to form the hard clot. Subsequently, plasmatocytes induce scab formation by spreading and sealing the clot from the haemocoel. Finally, epidermis regenerates, grows and replaces the scab (15).
Arthropod vectors, viruses, and innate immune responses
Mosquitoes
Mosquitoes (Diptera: Culicidae) are the vectors of pathogens that cause dengue, malaria, Japanese encephalitis, and filariasis (53). Out of 3000 documented mosquito species worldwide, more than 100 species are known to transmit infections to humans (54) (Figure 2). Mosquito-borne diseases are prevalent worldwide and infect over 0.7 billion population annually (54). Immune responses in vectors and vaccine strategies have been studied to circumvent the disease outbreaks (55, 56).
Figure 2
Mosquitoes transmit viruses (Zika, yellow fever, chikungunya, dengue, and West Nile), nematodes (filariasis), and Plasmodium parasites (malaria) in humans.
Most mosquito-borne viruses are RNA viruses, which belong to families Flaviviridae, Togaviridae, and Bunyaviridae (Table 1). Dengue virus is a member of the family Flaviviridae that causes 390 million infections every year (8). Furthermore, other members of the Flaviviridae such as Zika virus, West Nile virus, yellow fever virus, and Japanese encephalitis virus are also a cause of global concern due to increasing incidence and geographic expansion (64). In addition, their circulation poses serious health threats, for example, Zika virus has been linked to Guillain-Barré syndrome in adults and birth defects (microcephaly in prenatally infected infants) (65).
Table 1
| Family | Genus | Virus | Vector | Reference |
|---|---|---|---|---|
| Flaviridae | Flavivirus | Dengue virus | Aedes aegypti | (57) |
| Flavivirus | Zika virus | Aedes spp. | (7) | |
| Flavivirus | West Nile virus | Culex spp. | (58) | |
| Flavivirus | Yellow fever virus | Aedes spp. | (57) | |
| Flavivirus | Murray Valley encephalitis virus | Culex annulirostris | (59) | |
| Flavivirus | Japanese encephalitis virus | Aedes spp. | (57) | |
| Flavivirus | St. Louis encephalitis virus | Culex spp. | (60) | |
| Togaviridae | Alphavirus | Chikungunya virus | Aedes spp. | (61) |
| Alphavirus | Venezuelan equine encephalitis virus | Aedes spp. | (61) | |
| Alphavirus | Semliki Forest virus | Aedes spp. | (62) | |
| Alphavirus | O’nyong nyong virus | Anopheles spp. | (63) | |
| Bunyaviridae | Orthobunyavirus | La Crosse virus | Aedes triseriatus | (61) |
| Phlebovirus | Rift Valley fever virus | Aedes spp. | (61) |
Mosquito-borne viruses.
In mosquitoes, virus enters the midgut when it ingests the infected blood meal. The antiviral defense mechanism of mosquitoes is triggered as the virus is recognized by PRRs; however, the dissemination of the virus to the salivary glands is poorly understood (8). It is assumed that when the virus enters midgut epithelium, it replicates in the tissue and subsequently it gets disseminated to the haemocoel (66). The virus may spread through the haemolymph circulation to other tissues/organs including salivary glands, trachea, and neural tissues (21, 67) (Figure 3). The translocation of the virus to the salivary glands is crucial for their transmission to vertebrate hosts (68, 69).
Figure 3
Ingestion, replication, and dissemination of virus in the mosquito, (A) mosquito ingests the blood of infected host, (B) ingested virus infects the midgut (C) after replication in the midgut virus spreads in the haemocoel, (D) after dissemination virus infects salivary glands (E) finally mosquito transmits virus to host by biting it.
In mosquitoes, during viral infection, PRRs recognize virus-conserved PAMPs to instigate immune responses. Degradation and thereby inhibition of viral replication occurs through activation of the RNAi pathway which is the main antiviral mechanism (70). Despite antiviral defense mechanisms that hinder/limit viral replication, the immune system of the mosquito may not be able to effectively clear the virus (8, 71). Without significant lethal effects of viral infection to hosts (mosquitoes), mosquitoes tolerate/resist long-lasting infections that make them efficient vectors for the emergence or re-emergence of viral diseases. Therefore, to conceptualize anti-vectorial strategies, understanding the mechanisms of mosquito tolerance/resistance to viral infection is vital. Furthermore, we can develop novel anti-vector strategies such as use of genetically modified mosquitoes (72–76) and Wolbachia-infected mosquitoes (77–80) for resistance to viral pathogens to prevent human infections through understanding of the innate immune responses of mosquitoes (8). In 2021, in United States, first genetically engineered mosquitoes were released in a field trial after many years of fight for regulatory approval and its public acceptance for controlling populations of wild mosquitoes (Aedes aegypti), which carry viruses such as chikungunya, dengue, yellow fever, and Zika (81). Aedes aegypti was transinfected with the endosymbiont Wolbachia pipientis as a vector control strategy for dengue virus transmission. The Wolbachia infected mosquitoes showed a decreased biting success due to bendy proboscis (78), therefore limit virus transmission in populations. Furthermore, Wolbachia-harboring mosquitoes could reduce Zika virus transmission and can be effective vector control strategy (79).
Ticks
Ticks are responsible for the transmission of a variety of pathogens that cause diseases in humans and animals (82–84), including various arboviruses (85–87). However, the majority of human viral diseases transmitted by tick vectors are caused by flaviviruses, while other tick-borne viruses belong to other families such as Asfarviridae, Bunyaviridae, Flaviridae, Orthomyxoviridae, and Reoviridae (88) (Table 2). Tick-borne viruses are mostly RNA viruses that replicate in ticks as well as in vertebrate cells (86); however, antiviral innate immune mechanism is yet to be explored.
Table 2
| Family | Genus | Virus | Vector | Reference |
|---|---|---|---|---|
| Flaviridae | Flavivirus | Alkhurma hemorrhagic fever virus | Ornithodoros savignyi | (89) |
| Flavivirus | Kyasanur Forest disease virus | Haemaphysalis spp. | (57) | |
| Flavivirus | Tick-borne encephalitis virus | Ixodes spp. | (57) | |
| Flavivirus | Powassan virus | Ixodes spp. | (90) | |
| Flavivirus | Omsk haemorrhagic fever | Dermacentor spp. | (91) | |
| Flavivirus | Louping ill | Ixodes spp. | (92) | |
| Flavivirus | Kadam virus | Hyalomma dromedarii | (93) | |
| Flavivirus | Langat virus | Ixodes spp. | (94) | |
| Bunyaviridae | Phlebovirus | Heartland virus | Amblyomma spp. | (95) |
| Phlebovirus | Severe fever with thrombocytopenia syndrome virus | Haemaphysalis spp. | (96) | |
| Phlebovirus | Uukuniemi virus | Ixodes spp. | (97) | |
| Nairovirus | Crimean-Congo haemorrhagic fever virus | Hyalomma spp. | (5) | |
| Nairovirus | Nairobi sheep disease virus | Rhipicephalus appendiculatus | (5) | |
| Orthomyxoviridae | Thogotovirus | Thogoto virus | Rhipicephalus spp. | (98) |
| Reoviridae | Orbivirus | Tribec virus | Ixodes spp. | (99) |
| Orbivirus | Kemerovo virus | Ixodes spp. | (99) | |
| Coltivirus | Colorado tick fever virus | Dermacentor andersoni | (100) | |
| Asfarviridae | Asfivirus | African swine fever virus | Ornithodoros spp. | (101) |
Tick-borne viruses.
After mosquitoes, ticks are the second most important arthropod vectors (102), feeding on the blood of various vertebrate hosts including birds, mammals, amphibians and reptiles (103). Tick feeding can cause anemia in vertebrate hosts as a single adult female hard tick is able to consume more than 1 mL of blood (104), thereby adversely impacting on livestock health and productivity.
Tick feeding can also result in virus transmission. In the natural ecosystem, ticks become infected during viremic and non-viremic transmissions. In the case of viremic transmission, ticks become infected by feeding on the viremic vertebrate, whereas non-viremic transmission occurs when virus from an infected tick is transferred to an uninfected tick during co-feeding in a contained area on the skin of vertebrate host (88). During feeding, ticks secrete salivary molecules (105) that contain a mixture of proteins, peptides and non-peptide molecules that modulate host hemostasis and immune responses (106). Tick saliva can facilitate the transmission of viruses and other pathogens to the host during blood feeding by modulating host immune response (107). However, how pathogens evade different protective pathways and persist in the vector need to be explored. Tick-borne pathogens such as Anaplasma, Borrelia burgdorferi sensu lato, Ehrlichia, Francisella, and relapsing fever spirochetes have evolved various immune evasion strategies such as altering surface components, complement inhibition, antimicrobial molecule blocking, and inhibiting cytokines (108). Several tick-borne microbes modulate their outer-surface constituents via differential expression of various surface proteins through transcriptional regulation and intragenic recombination. Therefore, alteration of surface antigens allows microorganisms, for example, B. burgdorferi and relapsing fever spirochetes, to evade neutralizing host antibody response and encourage persistent infections in animals (109, 110). Surface components of bacteria may serve as PAMPs through recognition by TLRs (Toll-like receptors). Certain pathogens, for example Francisella tularensis mask their surfaces (to evade immune sensing) by synthesizing a carbohydrate-based capsule that inhibits the antibody and complement deposition on the cell wall, and provide protection against microbicidal host responses (for instance, opsonization) (111). Some bacteria, for example, B. burgdorferi and Anaplasma use host lipids (as a building block for the biogenesis of their membranes) that helps in bypassing host immune responses by avoiding the immune cells (108, 112). The cytokines play crucial roles in the integration of the innate and adaptive immune responses that are important for host defense against pathogens; various tick-borne microbes inhibit or enhance cytokine expression (108). For example, Anaplasma phagocytophilum infection leads to disruption of the IFN-γ (interferon-gamma) signaling pathways and downstream phagocytosis events by neutrophils (113). Ehrlichia chaffeensis may change early immune responses by inhibiting transcription of interleukin (IL)-12, IL-15, and IL-18 genes that allow Ehrlichia survival in macrophages (114). Borrelia burgdorferi or A. phagocytophilum infections trigger ticks (Ixodes) JAK/STAT or IMD pathways that stimulate a robust microbicidal response (115, 116). Anaplasma phagocytophilum activates the expression of tick antifreeze glycoprotein (IAFGP), which enhances the cold tolerance and survival of Ixode scapularis that eventually assist in persistence of pathogen in nature (117). Furthermore, A. phagocytophilum may modulate expression of salivary gland proteins (such as Salp16 and P11) from I. scapularis that aid its survival (118, 119). A pathogen ingested within the blood meal interacts with the tick gut (Figure 4) (104), colonizes the gut epithelial cells and/or crosses the gut epithelium to enter the haemocoel and may spread through haemolymph circulation to all tissues and organs (104). In haemolymph, complement-like molecules such as C3, C4, and C5 proteins opsonise pathogens that can be phagocytosed by haemocytes (30). Pathogens can also be destroyed by various types of effector molecules including AMPs, complement-like molecules, and factors of redox metabolism. Thereafter, the pathogen reaches the salivary glands to successfully transmit through saliva to the vertebrate host during the next blood feeding. Some pathogens, e.g. bacteria, also have the ability to invade tick ovaries and may transmit to progeny trans-ovarially (Figure 4). In the tick’s salivary glands, ovaries and midgut, pathogens have to deal with resident microorganisms as well as tick immune responses that impact the vector competence. Understanding the immune factors involved in interactions between ticks and tick-borne pathogens is essential to delineate the biology of tick-transmitted diseases and could help to detect targets for developing new strategies to block pathogen transmission (120). The acquisition, development, and transmission of diseases by ticks are explained in Figure 4.
Figure 4
Acquisition, development, and transmission of pathogens by ticks. 1. When ticks bite, pathogens are ingested with the meal. 2. Pathogens either stay until the next meal or move through the gastrointestinal epithelium 3. The extraneous pathogen can potentially harm the tick’s body, depending on the type of pathogen. 4. Pathogens enter the salivary gland and attack the acini through the epithelium. 5,6. Pathogens, along with saliva, are introduced into a new host during feeding, disrupting host homeostasis and setting off inflammatory responses.
To understand host-virus interaction, studies have been performed by injecting virus into D. melanogaster flies (121). This method has been shown to be relevant for identifying pathogen virulence factors and host defense mechanisms; however, injecting the virus amounts to bypassing the hosts’ natural protection barriers. Various studies have revealed that the transmission route used by pathogens has a substantial impact on the intensity of an infection and differential immune responses (122, 123). Drosophila and mosquitoes have a holometabolous life-cycle; they undergo metamorphosis between four life stages: egg, larva, pupa, and imago (adult), whereas ticks exhibit hemimetabolous development with life-cycles consisting of four stages: egg, larva, nymph and adult (103). The pathogen tropism and infection outcome may thus depend on the route of infection of the pathogen and the developmental stages of the arthropod (123, 124).
Conclusion
Presently, treatments are available for many vector-borne viral diseases. However, vaccines are not available for the majority of mosquito- or tick-transmitted viral diseases. There is a focus on diagnosis, treatment and on vector control strategies to help prevent viral disease transmission and spread. In the case of mosquitoes, field tests are being conducted on the utility of genetically modified mosquitoes for control, however, there are concerns regarding the introduction of transgenic organisms into the wild. This approach is new and there is limited knowledge about how mosquito antiviral defense mechanisms may evolve with this strategy. The tick immune system and antiviral defense responses remain poorly understood. It is crucial to know how the mosquito and tick innate immune systems respond to viral infection and replication, and how the viruses are actually transmitted to a healthy mammalian host, which may help in the development of novel strategies to block or control vector-borne virus transmission. A continued integration of the expertise of ecologists, animal virologists, immunologists, entomologists, molecular biologists, geneticists, and public health personnel are required to achieve optimal health outcome for human, animals and the environment, and to eliminate the risk of these vector-borne diseases in the future.
Statements
Author contributions
Conceptualization: NP, AW, and UK. Writing—original draft preparation: NP. Writing—review and editing: NP, UK, AW, KM, SM, OS, BG, and NM. Visualization: NP, TZ, UK, and KM. Supervision: AW. Project administration: AW. All authors contributed to the article, read and approved the final manuscript. All authors contributed to the article and approved the submitted version.
Funding
The funding of this study was provided by the UAE University through UPAR Grant # G00003709 to AW.
Acknowledgments
We also appreciate the library facility provided by the United Arab Emirates University.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1
TereniusO. Anti-parasitic and anti-viral immune responses in insects. Ph D Thesis Dep Genet Microbiol Toxicol Stock Univ Stock Sweden (2004). p. 68.
2
StorkNE. How many species of insects and other terrestrial arthropods are there on earth? Annu Rev Entomol (2018) 63:31–45. doi: 10.1146/annurev-ento-020117-043348
3
MartelliFZhongyuanZWangJWongCOKaragasNERoessnerUet al. Low doses of the neonicotinoid insecticide imidacloprid induce ROS triggering neurological and metabolic impairments in drosophila. Proc Natl Acad Sci U.S.A. (2020) 117:25840–50. doi: 10.1073/pnas.2011828117
4
BaxterRHGContetAKruegerK. Arthropod innate immune systems and vector-borne diseases. Biochemistry (2017) 56:907–18. doi: 10.1021/acs.biochem.6b00870
5
LabudaMNuttallPA. Tick-borne viruses. Parasitology (2004) 129:S221–45. doi: 10.1017/S0031182004005220
6
ShiJHuZDengFShenS. Tick-borne viruses. Virol Sin (2018) 33:21–43. doi: 10.1007/s12250-018-0019-0
7
PaixãoESTeixeiraMGRodriguesLC. Zika, chikungunya and dengue: The causes and threats of new and reemerging arboviral diseases. BMJ Glob Heal (2018) 3:1–6. doi: 10.1136/bmjgh-2017-000530
8
LeeWSWebsterJAMadzokereETStephensonEBHerreroLJ. Mosquito antiviral defense mechanisms: A delicate balance between innate immunity and persistent viral infection. Parasites Vectors (2019) 12:1–12. doi: 10.1186/s13071-019-3433-8
9
RibeiroCBrehélinM. Insect haemocytes: What type of cell is that? J Insect Physiol (2006) 52:417–29. doi: 10.1016/j.jinsphys.2006.01.005
10
PandeyJPTiwariRK. An overview of insect hemocyte science and its future application in applied and biomedical fields. Amer J Biochem Mol Biol (2012) 2:82–105. doi: 10.3923/ajbmb.2012.82.105
11
BrowneNHeelanMKavanaghK. An analysis of the structural and functional similarities of insect hemocytes and mammalian phagocytes. Virulence (2013) 4:597–603. doi: 10.4161/viru.25906
12
SapcaliuARadoiIPavelCTudorNCauiaESiceanuAet al. Research regarding haemocyte profile from apis mellifera carpatica bee haemolymph originated in the south of Romania. Lucr stiinłifice Med Vet (2009) 42(2):393–7.
13
StrandMR. Insect hemocytes and their role in immunity. Insect Immunol (2008), 25–47. doi: 10.1016/B978-0-12-373976-6.50004-5
14
HansonMAHamiltonPTPerlmanSJ. Immune genes and divergent antimicrobial peptides in flies of the subgenus drosophila. BMC Evol Biol (2016) 16:1–14. doi: 10.1186/s12862-016-0805-y
15
LavineMDStrandMR. Insect hemocytes and their role in immunity. Insect Biochem Mol Biol (2002) 32:1295–309. doi: 10.1016/B978-012373976-6.50004-5
16
SchmidtOTheopoldUStrandM. Innate immunity and its evasion and suppression by hymenopteran endoparasitoids. BioEssays (2001) 23:344–51. doi: 10.1002/bies.1049
17
SatyavathiVVMinzANagarajuJ. Nodulation: An unexplored cellular defense mechanism in insects. Cell Signal (2014) 26:1753–63. doi: 10.1016/j.cellsig.2014.02.024
18
NainuFTanakaYShiratsuchiANakanishiY. Protection of insects against viral infection by apoptosis-dependent phagocytosis. J Immunol (2015) 195:5696–706. doi: 10.4049/jimmunol.1500613
19
TsuzukiSMatsumotoHFurihataSRyudaMTanakaHSungEJet al. Switching between humoral and cellular immune responses in drosophila is guided by the cytokine GBP. Nat Commun (2014) 5:1–11. doi: 10.1038/ncomms5628
20
SantiagoPBDe AraújoCNMottaFNPraçaYRCharneauSBastosIMDet al. Proteases of haematophagous arthropod vectors are involved in blood-feeding, yolk formation and immunity - a review. Parasites Vectors (2017) 10:1–20. doi: 10.1186/s13071-017-2005-z
21
XiZRamirezJLDimopoulosG. The aedes aegypti toll pathway controls dengue virus infection. PloS Pathog (2008) 4:1–12. doi: 10.1371/journal.ppat.1000098
22
WengSCLiHHLiJCLiuWLChenCHShiaoSH. A thioester-containing protein controls dengue virus infection in aedes aegypti through modulating immune response. Front Immunol (2021) 12:670122. doi: 10.3389/fimmu.2021.670122
23
StokesBAYadavSShokalUSmithLCEleftherianosI. Bacterial and fungal pattern recognition receptors in homologous innate signaling pathways of insects and mammals. Front Microbiol (2015) 6:19. doi: 10.3389/fmicb.2015.00019
24
GoicBStaplefordKAFrangeulLDoucetAJGaussonVBlancHet al. Virus-derived DNA drives mosquito vector tolerance to arboviral infection. Nat Commun (2016) 7:1–10. doi: 10.1038/ncomms12410
25
HillyerFJ. Insect immunology and hematopoiesis. Dev Comp Immunol 2016 (2016) 58:102–18. doi: 10.1016/j.dci.2015.12.006.Insect
26
RämetMManfruelliPPearsonAMathey-PrevotBEzekowitzRAB. Functional genomic analysis of phagocytosis and identification of a drosophila receptor for e. Coli. Nat (2002) 416:644–8. doi: 10.1038/nature735
27
HillyerJFStrandMR. Mosquito hemocyte-mediated immune responses. Curr Opin Insect Sci (2014) 3:14–21. doi: 10.1016/j.cois.2014.07.002
28
JiravanichpaisalPLeeBLSöderhällK. Cell-mediated immunity in arthropods: Hematopoiesis, coagulation, melanization and opsonization. Immunobiology (2006) 211:213–36. doi: 10.1016/j.imbio.2005.10.015
29
PoinarGOLeuteneggerRGötzP. Ultrastructure of the formation of a melanotic capsule in diabrotica (Coleoptera) in response to a parasitic nematode (Mermithidae). J Ultrasructure Res (1968) 25:293–306. doi: 10.1016/S0022-5320(68)80075-9
30
ShokalUEleftherianosI. Evolution and function of thioester-containing proteins and the complement system in the innate immune response. Front Immunol (2017) 8:759. doi: 10.3389/fimmu.2017.00759
31
ChristensenBMLiJChenCCNappiAJ. Melanization immune responses in mosquito vectors. Trends Parasitol (2005) 21:192–9. doi: 10.1016/j.pt.2005.02.007
32
EleftherianosIHeryantoCBassalTZhangWTettamantiGMohamedA. Haemocyte-mediated immunity in insects: Cells, processes and associated components in the fight against pathogens and parasites. Immunology (2021) 164:401–32. doi: 10.1111/imm.13390
33
HillyerJFSchmidtSLChristensenBM. Hemocyte-mediated phagocytosis and melanization in the mosquito armigeres subalbatus following immune challenge by bacteria. Cell Tissue Res (2003) 313:117–27. doi: 10.1007/s00441-003-0744-y
34
HarshSTafesh-EdwardsGEleftherianosI. Zika virus infection triggers the melanization response in drosophila. Biochim Biophys Acta (BBA)-Molecular Basis Dis (2022) 1868:166424. doi: 10.1016/j.bbadis.2022.166424
35
LemaitreBHoffmannJ. The host defense of drosophila melanogaster. Annu Rev Immunol (2007) 25:697–743. doi: 10.1146/annurev.immunol.25.022106.141615
36
HaEMOhCTBaeYSLeeWJ. A direct role for dual oxidase in drosophila gut immunity. Sci (80- ) (2005) 310:847–50. doi: 10.1126/science.1117311
37
SweversLLiuJSmaggheG. Defense mechanisms against viral infection in drosophila: RNAi and non-RNAi. Viruses (2018) 10:1–35. doi: 10.3390/v10050230
38
YuNChristiaensOLiuJNiuJCappelleKCacciaSet al. Delivery of dsRNA for RNAi in insects: An overview and future directions. Insect Sci (2013) 20:4–14. doi: 10.1111/j.1744-7917.2012.01534.x
39
BlairCDOlsonKE. Mosquito immune responses to arbovirus infections. Curr Opin Insect Sci (2014) 3:22–9. doi: 10.1016/j.cois.2014.07.005
40
DingSWVoinnetO. Antiviral immunity directed by small RNAs. Cell (2007) 130:413–26. doi: 10.1016/j.cell.2007.07.039
41
BronkhorstAWvan RijRP. The long and short of antiviral defense: Small RNA-based immunity in insects. Curr Opin Virol (2014) 7:19–28. doi: 10.1016/j.coviro.2014.03.010
42
DeddoucheSMattNBuddAMuellerSKempCGaliana-ArnouxDet al. The DExD/H-box helicase dicer-2 mediates the induction of antiviral activity in drosophila. Nat Immunol (2008) 9:1425–32. doi: 10.1038/ni.1664
43
RückertCBell-SakyiLFazakerleyJKFragkoudisR. Antiviral responses of arthropod vectors: an update on recent advances. VirusDisease (2014) 25:249–60. doi: 10.1007/s13337-014-0217-9
44
SiomiMCSatoKPezicDAravinAA. PIWI−interacting small RNAs: the vanguard of genome defence. Nat Rev Mol Cell Biol (2011) 12:246–58. doi: 10.1038/nrm3089
45
ElmoreS. Apoptosis: A review of programmed cell death. Toxicol Pathol (2007) 35:495–516. doi: 10.1080/01926230701320337
46
ClarkeTEClemRJ. Insect defenses against virus infection: The role of apoptosis. Int Rev Immunol (2003) 22:401–24. doi: 10.1080/08830180305215
47
IgneyFHKrammerPH. Death and anti-death: Tumour resistance to apoptosis. Nat Rev Cancer (2002) 2:277–88. doi: 10.1038/nrc776
48
YanoTKurataS. Intracellular recognition of pathogens and autophagy as an innate immune host defence. J Biochem (2011) 150:143–9. doi: 10.1093/jb/mvr083
49
MoyRHCherryS. Antimicrobial autophagy: A conserved innate immune response in drosophila. J Innate Immun (2013) 5:444–55. doi: 10.1159/000350326
50
ShibutaniSTSaitohTNowagHMünzCYoshimoriT. Autophagy and autophagy-related proteins in the immune system. Nat Immunol (2015) 16:1014–24. doi: 10.1038/ni.3273
51
YanoTMitaSOhmoriHOshimaYFujimotoYUedaRet al. Autophagic control of listeria through intracellular innate immune recognition in drosophila. Nat Immunol (2008) 9:908–16. doi: 10.1038/ni.1634
52
MoyRHGoldBMollestonJMSchadVYangerKSalzanoMVet al. Antiviral autophagy restricts rift valley fever virus infection and is conserved from flies to mammals. Immunity (2014) 40:51–65. doi: 10.1016/j.immuni.2013.10.020
53
PrudêncioM. In fairness to mosquitoes. Trends Parasitol (2020) 36:876–7. doi: 10.1016/j.pt.2020.08.003
54
TehriKSinghN. The role of botanicals as green pesticides in integrated mosquito management – a review. Int J Mosq Res (2015) 2:18–23.
55
FerlugaJSinghIRoutSAl-QahtaniAYasminHKishoreU. Immune responses in malaria and vaccine strategies. Adv Exp Med Biol (2021) 1313:273–91. doi: 10.1007/978-3-030-67452-6_12
56
YasminHAdhikaryAAl-AhdalMNRoySKishoreU. Host–pathogen interaction in leishmaniasis: Immune response and vaccination strategies. Immuno (2022) 2:218–54. doi: 10.3390/immuno2010015
57
GouldEASolomonT. Pathogenic flaviviruses. Lancet (2008) 371:500–9. doi: 10.1016/S0140-6736(08)60238-X
58
KramerLDLiJShiPY. West Nile Virus. Lancet Neurol (2007) 6:171–81. doi: 10.1016/S1474-4422(07)70030-3
59
BroomAKLindsayMDPlantAJWrightAECondonRJMackenzieJS. Epizootic activity ofMurray valley encephalitis virus in an aboriginal community in the southeast Kimberley region of Western Australia: results of cross-sectional and longitudinal serologic studies. Am J Trop Med Hyg (2002) 67:319–23.
60
DayJF. Predicting st. Louis encephalitis virus epidemics: lessons from recent, and not so recent, outbreaks. Annu Rev Entomol (2001) 46:111–38.
61
HollidgeBSGonzález-ScaranoFSoldanSS. Arboviral encephalitides: Transmission, emergence, and pathogenesis. J Neuroimmune Pharmacol (2010) 5:428–42. doi: 10.1007/s11481-010-9234-7
62
MathiotCCGrimaudGGarryPBouquetyJCMadaADaguisyAMet al. An outbreak of human semliki forest virus infections in central African republic. Am J Trop Med Hyg (1990) 42:386–93. doi: 10.4269/ajtmh.1990.42.386
63
WilliamsMCWoodallJPCorbetPSGillettJD. O’nyong-nyong fever: An epidemic virus disease in East Africa VIII. virus isolations from anopheles mosquitoes. Trans R Soc Trop Med Hyg (1965) 59:300–6. doi: 10.1016/0035-9203(65)90012-X
64
TrammellCEGoodmanAG. Host factors that control mosquito-borne viral infections in humans and their vector. Viruses (2021) 13:1–16. doi: 10.3390/v13050748
65
WeaverSCCostaFGarcia-BlancoMAKoAIRibeiroGSSaadeGet al. Zika virus: History, emergence, biology, and prospects for control. Antiviral Res (2016) 130:69–80. doi: 10.1016/j.antiviral.2016.03.010
66
FranzAWEKantorAMPassarelliALClemRJ. Tissue barriers to arbovirus infection in mosquitoes. Viruses (2015) 7:3741–67. doi: 10.3390/v7072795
67
SalazarMIRichardsonJHSánchez-VargasIOlsonKEBeatyBJ. Dengue virus type 2: Replication and tropisms in orally infected aedes aegypti mosquitoes. BMC Microbiol (2007) 7:1–13. doi: 10.1186/1471-2180-7-9
68
BennettKEFlickDFlemingKHJochimRBeatyBJBlackWCIV. Quantitative trait loci that control dengue-2 virus dissemination in the mosquito aedes aegypti. Genetics (2005) 170:185–94. doi: 10.1534/genetics.104.035634
69
ChauhanCBehuraSKdeBruynBLovinDDHarkerBWGomez-MachorroCet al. Comparative expression profiles of midgut genes in dengue virus refractory and susceptible aedes aegypti across critical period for virus infection. PloS One (2012) 7:1–13. doi: 10.1371/journal.pone.0047350
70
WeiYHeYLZhengXL. Research progress in RNA interference against the infection of mosquito-borne viruses. Yi Chuan= Hered (2020) 42:153–60. doi: 10.16288/j.yczz.19-262
71
ChengGLiuYWangPXiaoX. Mosquito defense strategies against viral infection. Trends Parasitol (2016) 32:177–86. doi: 10.1016/j.pt.2015.09.009
72
WilkeABBde Castro GomesANatalDMarrelliMT. Control of vector populations using genetically modified mosquitoes. Rev Saude Publica (2009) 43:869–74. doi: 10.1590/S0034-89102009005000050
73
OkoriePNMarshallJMAkpaOMAdemowoOG. Perceptions and recommendations by scientists for a potential release of genetically modified mosquitoes in Nigeria. Malar J (2014) 13:1–8. doi: 10.1186/1475-2875-13-154
74
TouréYTOduolaAMSommerfeldJMorelCM. Biosafety and risk assessment in the use of genetically modified mosquitoes for disease control. Frontis (2004) 2:217–22.
75
RamseyJMBondJGMacotelaMEFacchinelliLValerioLBrownDMet al. A regulatory structure for working with genetically modified mosquitoes: Lessons from Mexico. PloS Negl Trop Dis (2014) 8:1–9. doi: 10.1371/journal.pntd.0002623
76
MarshallJM. The cartagena protocol and genetically modified mosquitoes. Nat Biotechnol (2010) 28:896–7. doi: 10.1038/nbt0910-896
77
AndersKLIndrianiCAhmadRATantowijoyoWArguniEAndariBet al. Update to the AWED (Applying wolbachia to eliminate dengue) trial study protocol: A cluster randomised controlled trial in yogyakarta, Indonesia. Trials (2020) 21:1–16. doi: 10.1186/s13063-020-04367-2
78
TurleyAPMoreiraLAO’NeillSLMcGrawEA. Wolbachia infection reduces blood-feeding success in the dengue fever mosquito, aedes aegypti. PloS Negl Trop Dis (2009) 3:1–6. doi: 10.1371/journal.pntd.0000516
79
DutraHLCRochaMNDiasFBSMansurSBCaragataEPMoreiraLA. Wolbachia blocks currently circulating zika virus isolates in Brazilian aedes aegypti mosquitoes. Cell Host Microbe (2016) 19:771–4. doi: 10.1016/j.chom.2016.04.021
80
O’ReillyKMHendrickxEKharismaDDWilastonegoroNNCarringtonLBElyazarIRFet al. Estimating the burden of dengue and the impact of release of wMel wolbachia-infected mosquitoes in Indonesia: A modelling study. BMC Med (2019) 17:1–14. doi: 10.1186/s12916-019-1396-4
81
WaltzE. First genetically modified mosquitoes released in the united states. Nature (2021) 593:175–6. doi: 10.1038/d41586-021-01186-6
82
JongejanFUilenbergG. Ticks and control methods. Rev Sci tech Off Int Epiz (1994) 13:1201–26. doi: 10.20506/rst.13.4.818
83
JongejanFUilenbergG. The global importance of ticks. Parasitology (2004) 129:S3–S14. doi: 10.1017/S0031182004005967
84
PerveenNMuzaffarSBAl-DeebMA. Ticks and tick-borne diseases of livestock in the middle East and north Africa: A review. Insects (2021) 12:1–34. doi: 10.3390/insects12010083
85
de la FuenteJAntunesSBonnetSCabezas-cruzA. Tick-pathogen interactions and vector Competence : Identification of molecular drivers for tick-borne diseases. Front Cell Infect Microbiol (2017) 7:114. doi: 10.3389/fcimb.2017.00114
86
KazimírováMThangamaniSBartíkováPHermanceMHolíkováVŠtibrániováIet al. Tick-borne viruses and biological processes at the tick-Host-Virus interface. Front Cell Infect Microbiol (2017) 7:339. doi: 10.3389/fcimb.2017.00339
87
TalactacMRHernandezEPHattaTYoshiiKKusakisakoKTsujiNet al. The antiviral immunity of ticks against transmitted viral pathogens. Dev Comp Immunol (2021) 119:104012. doi: 10.1016/j.dci.2021.104012
88
GrabowskiJMOfferdahlDKBloomME. The use of ex vivo organ cultures in tick-borne virus research. ACS Infect Dis (2018) 4:247–56. doi: 10.1021/acsinfecdis.7b00274
89
CharrelRNFagboSMoureauG. Alkhurma hemorrhagic fever virus in ornithodoros savignyi ticks. Emerg Infect Dis (2007) 13:153–5. doi: 10.3201/eid1301.061094
90
EbelGD. Update on powassan virus: Emergence of a north American tick-borne flavivirus. Annu Rev Entomol (2010) 55:95–110. doi: 10.1146/annurev-ento-112408-085446
91
RůžekDYakimenkoVVKaranLSTkachevSE. Omsk haemorrhagic fever. Lancet (2010) 376:2104–13. doi: 10.1016/S0140-6736(10)61120-8
92
JeffriesCLMansfieldKLPhippsLPWakeleyPRMearnsRSchockAet al. Louping ill virus: An endemic tick-borne disease of great Britain. J Gen Virol (2014) 95:1005–14. doi: 10.1099/vir.0.062356-0
93
WoodOLMoussaMIHoogstraalHBüttikerW. Kadam virus (Togaviridae, flavivirus) infecting camel-parasitizing hyalomma dromedarii ticks (Acari: Ixodidae) in Saudi Arabia. J Med Entomol (1982) 19:207–8. doi: 10.1093/jmedent/19.2.207
94
RumyantsevAAMurphyBRPletnevAG. A tick-borne langat virus mutant that is temperature sensitive and host range restricted in neuroblastoma cells and lacks neuroinvasiveness for immunodeficient mice. J Virol (2006) 80:1427–39. doi: 10.1128/jvi.80.3.1427-1439.2006
95
SavageHMGodseyMSAmyLPanellaNABurkhalterKLHarmonJRet al. First detection of heartland virus (bunyaviridae: Phlebovirus) from field collected arthropods. Am J Trop Med Hyg (2013) 89:445–52. doi: 10.4269/ajtmh.13-0209
96
YuX-JLiangM-FZhangS-YLiuYLiJ-DSunY-Let al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med (2011) 364:1523–32. doi: 10.1056/nejmoa1010095
97
HubálekZRudolfI. Tick-borne viruses in Europe. Parasitol Res (2012) 111:9–36. doi: 10.1007/s00436-012-2910-1
98
HaigDAWoodallJPDanskinD. Thogoto virus: a hitherto underscribed agent isolated from ticks in. J Gen Microbiol (1965) 38:389–94. doi: 10.1099/00221287-38-3-389
99
DilcherMHasibLLechnerMWiesekeNMiddendorfMMarzMet al. Genetic characterization of tribeč virus and kemerovo virus, two tick-transmitted human-pathogenic orbiviruses. Virology (2012) 423:68–76. doi: 10.1016/j.virol.2011.11.020
100
AttouiHJaafarFMDe MiccoPDe LamballerieX. Coltiviruses and seadornaviruses in north America, Europe, and Asia. Emerg Infect Dis (2005) 11:1673–9. doi: 10.3201/eid1111.050868
101
DixonLKChapmanDAGNethertonCLUptonC. African Swine fever virus replication and genomics. Virus Res (2013) 173:3–14. doi: 10.1016/j.virusres.2012.10.020
102
ParolaPRaoultD. Ticks and tickborne bacterial diseases in humans: An emerging infectious threat. Clin Infect Dis (2001) 32:897–928. doi: 10.1086/319347
103
SonenshineDERoeRM. Ticks, people, and animals. In: Biology of ticks volume 1. (2013) New York: Oxford University Press.
104
FogaçaACSousaGPavaneloDBEstevesEMartinsLAUrbanováVet al. Tick immune system: What is known, the interconnections, the gaps, and the challenges. Front Immunol (2021) 12:628054. doi: 10.3389/fimmu.2021.628054
105
BowmanASSauerJR. Tick salivary glands: Function, physiology and future. Parasitology (2004) 129:S67–81. doi: 10.1017/S0031182004006468
106
KotálJLanghansováHLieskovskáJAndersenJFFrancischettiIMBChavakisTet al. Modulation of host immunity by tick saliva. J Proteomics (2015) 128:58–68. doi: 10.1016/j.jprot.2015.07.005
107
KazimírováMŠtibrániováI. Tick salivary compounds: Their role in modulation of host defences and pathogen transmission. Front Cell Infect Microbiol (2013) 4:43. doi: 10.3389/fcimb.2013.00043
108
RanaVSKitsouCDumlerJSPalU. Immune evasion strategies of major tick-transmitted bacterial pathogens. Trends Microbiol (2023) 31(1):62–75. doi: 10.1016/j.tim.2022.08.002
109
Ting LiangFJacobsMBBowersLCPhilippMT. An immune evasion mechanism for spirochetal persistence in Lyme borreliosis. J. Exp. Med. (2002) 195(4):415–42. doi: 10.1084/jem.20011870
110
PorcellaSFRaffelSJAndersonDEGilkSDBonoJLSchrumpfMEet al. Variable tick protein in two genomic groups of the relapsing fever spirochete borrelia hermsii in Western north America. Infect Immun (2005) 73:6647–58. doi: 10.1128/IAI.73.10.6647-6658.2005
111
Freudenberger CatanzaroKCInzanaTJ. The francisella tularensis polysaccharides: What is the real capsule? Microbiol Mol Biol Rev (2020) 84:1–18. doi: 10.1128/mmbr.00065-19
112
ToledoABenachJL. Hijacking and use of host lipids by intracellular pathogens. Virulence Mech Bact Pathog (2016) 3:635–66. doi: 10.1128/9781555819286.ch22
113
JohnsJLMacNamaraKCWalkerNJWinslowGMBorjessonDL. Infection with anaplasma phagocytophilum induces multilineage alterations in hematopoietic progenitor cells and peripheral blood cells. Infect Immun (2009) 77:4070–80. doi: 10.1128/IAI.00570-09
114
MoumèneAMeyerDF. Ehrlichia’s molecular tricks to manipulate their host cells. Microbes Infect (2016) 18:172–9. doi: 10.1016/j.micinf.2015.11.001
115
ShawDKWangXBrownLJChávezASOReifKESmithAAet al. Infection-derived lipids elicit an immune deficiency circuit in arthropods. Nat Commun (2017) 8:1–13. doi: 10.1038/ncomms14401
116
SmithAANavasaNYangXWilderCNBuyuktanirOMarquesAet al. Cross-species interferon signaling boosts microbicidal activity within the tick vector. Cell Host Microbe (2016) 20:91–8. doi: 10.1016/j.chom.2016.06.001
117
AbrahamNMLiuLJutrasBLYadavAKNarasimhanSGopalakrishnanVet al. Pathogen-mediated manipulation of arthropod microbiota to promote infection. Proc Natl Acad Sci U.S.A. (2017) 114:E781–90. doi: 10.1073/pnas.1613422114
118
SukumaranBNarasimhanSAndersonJFDePonteKMarcantonioNKrishnanMNet al. An ixodes scapularis protein required for survival of anaplasma phagocytophilum in tick salivary glands. J Exp Med (2006) 203:1507–17. doi: 10.1084/jem.20060208
119
LiuLNarasimhanSDaiJZhangLChengGFikrigE. Ixodes scapularis salivary gland protein P11 facilitates migration of anaplasma phagocytophilum from the tick gut to salivary glands. EMBO Rep (2011) 12:1196–203. doi: 10.1038/embor.2011.177
120
Schorderet-WeberSNoackSSelzerPMKaminskyR. Blocking transmission of vector-borne diseases. Int J Parasitol Drugs Drug Resist (2017) 7:90–109. doi: 10.1016/j.ijpddr.2017.01.004
121
JenningsBH. Drosophila-a versatile model in biology & medicine. Mater Today (2011) 14:190–5. doi: 10.1016/S1369-7021(11)70113-4
122
GuptaVVasanthakrishnanRBSiva-JothyJMonteithKMBrownSPValePF. The route of infection determines wolbachia antibacterial protection in drosophila. Proc R Soc B Biol Sci (2017) 284:1–9. doi: 10.1098/rspb.2017.0809
123
MartinsNEFariaVGTeixeiraLMagalhãesSSucenaÉ. Host adaptation is contingent upon the infection route taken by pathogens. PloS Pathog (2013) 9:1–8. doi: 10.1371/journal.ppat.1003601
124
MondotteJASalehMC. Antiviral immune response and the route of infection in drosophila melanogaster. Adv Virus Res (2018) 100:247–78. doi: 10.1016/bs.aivir.2017.10.006
Summary
Keywords
immune system, innate immunity, virus circulation, haemocoel, haemocytes, antiviral defense
Citation
Perveen N, Muhammad K, Muzaffar SB, Zaheer T, Munawar N, Gajic B, Sparagano OA, Kishore U and Willingham AL (2023) Host-pathogen interaction in arthropod vectors: Lessons from viral infections. Front. Immunol. 14:1061899. doi: 10.3389/fimmu.2023.1061899
Received
05 October 2022
Accepted
17 January 2023
Published
31 January 2023
Volume
14 - 2023
Edited by
Balachandran Ravindran, Institute of Life Sciences (ILS), India
Reviewed by
Taruna Madan, National Institute for Research in Reproductive Health (ICMR), India; Abhishek Shastri, Central and North West London NHS Foundation Trust, United Kingdom
Updates
Copyright
© 2023 Perveen, Muhammad, Muzaffar, Zaheer, Munawar, Gajic, Sparagano, Kishore and Willingham.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Arve Lee Willingham, awillingham@uaeu.ac.ae
This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology
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