Edited by: Fabrice Cognasse, INSERM U1059 SAnté INgéniérie BIOlogie, France
Reviewed by: Pio Conti, University of Studies G. d’Annunzio Chieti and Pescara, Italy; Adriana Bonomo, Oswaldo Cruz Foundation (Fiocruz), Brazil
*Correspondence: Sonia Sifuentes-Franco,
This article was submitted to Inflammation, a section of the journal Frontiers in Immunology
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With the appearance of the SARS-CoV-2 virus in December 2019, all countries in the world have implemented different strategies to prevent its spread and to intensively search for effective treatments. Initially, severe cases of the disease were considered in adult patients; however, cases of older school-age children and adolescents who presented fever, hypotension, severe abdominal pain and cardiac dysfunction, positive for SARS-CoV-2 infection, have been reported, with increased pro-inflammatory cytokines and tissue damage, condition denominated multisystemic inflammatory syndrome (MIS-C); The emerging data from patients with MIS-C have suggested unique characteristics in the immunological response and also clinical similarities with other inflammatory syndromes, which can support as a reference in the search for molecular mechanisms involved in MIS-C. We here in propose that oxidative stress (OE) may play a very important role in the pathophysiology of MIS-C, such as occurs in Kawasaki disease (KD), severe COVID-19 in adults and other processes with characteristics of vascular damage similar to MIS- C, for which we review the available information that can be correlated with possible redox mechanisms.
In December 2019, with the recent emergence of the new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has started to appear in China (
Coronaviruses (CoVs) are a family of enveloped ribonucleic acid (RNA) viruses that cause infections that are transmitted mainly through the respiratory and fecal-oral routes. This family of viruses is distinguished by the large size of its genome (
The SARS-CoV-2 is a recently identified beta-coronavirus with a size genome of 29.9 kb, encoding at least 29 proteins, four of which are structural proteins: the spike (S), membrane (M), envelope (E) and nucleocapsid (N) proteins (
The SARS-CoV-2 is transmitted by droplets generated during coughing and sneezing by infected people without adequate personal protection and hygiene, regardless of whether they are symptomatic or not (
Structure of the SARS-CoV-2 virus and molecular mechanisms in the inflammation process and oxidative stress. The binding of the S protein to a receptor ACER2 and the co-receptor TMPRSS2, allows the SARS-CoV-2 entry the alveolar epithelial cell. The recognition of SARS-CoV-2 in the macrophages, leads the accumulation of ROS and facilitates the activation of the NF-kB pathway, which results in an expression of pro-inflammatory cytokines that promote neutrophil activation. Figure created with BioRender, ©
The severity is highly variable among individuals infected with SARS-CoV-2, ranging from asymptomatic cases up to severe respiratory disease with extrapulmonary findings (
Initially, people over 65 years of age represented a population at high risk of complications, with approximately 50% of hospitalizations and up to 80% of deaths caused by COVID-19 (
The MIS-C is a systemic inflammation that comprises the heart, lungs, kidneys, brain, skin, eyes and gastrointestinal organs; the diagnostic criteria are shown in
Diagnostic criteria for PIMS-TS/MIS-C.
World Health Organization ( |
Royal College of Pediatrics and Child Health (UK) ( |
Centers for Disease Control and Prevention (US) ( |
---|---|---|
1. 0–19 years of age. |
1. Pediatric age group. |
1. An individual aged <21 years. |
NT-proBNP, N-terminal pro-brain natriuretic peptide; PT, prothrombin; PTT, partial thromboplastin time; KD, Kawasaki disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL, interleukin; LDH, lactate dehydrogenase; RT-PCR, reverse transcription-polymerase chain reaction.
Laboratory findings include lymphopenia and reduced to normal thrombocytes (
During the acute phase, there is lymphopenia of helper (CD4+), cytotoxic (CD8+) and γδ T cells. The count of total neutrophils, monocyte, dendritic cell and natural killer cells remains normal, despite the expression of molecules associated with their function changes. High levels of IL-8 could be related to increased neutrophil activation, which in turn could influence T and B lymphocyte responses. In contrast, molecules involved in antigen presentation have decreased expression on macrophages and dendritic cells, suggesting impaired function (
The OS is an imbalance between the production of RS and the endogenous antioxidant defense, indicating an imbalance of the pro-oxidant-antioxidant balance in favor of pro-oxidants (
OS has been implicated in different pathologies as a triggering factor of the pathophysiological process, such as kidney disease (
Most viral infections, after the invasion of host tissues, hijack cellular functions to initiate viral replication; however, the immune system can limit viral spread through the recognition of innate elements in the infected cells, followed by the activation of defense mechanisms to eradicate the infection
Some of these pathways increase the activity of type I IFN and inflammatory cytokines (
The NF-κB pathway is essential to regulate multiple cellular processes, especially inflammatory responses, apoptosis and the differentiation of immune system cells. Several factors can activate the NF-κB pathway, for example TNFα, lipopolysaccharide (LPS) and IL-1 (
In severe cases of COVID-19, there is a significant decrease in oxygen saturation (less than 90%), which produces significant hypoxic changes (
Another pathway that correlates OS with SARS-CoV2 infection is the Nrf-2 factor (nuclear factor erythroid-derived 2-related factor 2), which regulates approximately 250 genes involved in cell homeostasis, including antioxidant proteins and numerous cytoprotective proteins (
Both NF-κB and Nrf2 are regulated by oxidative factors: the blocking of Nrf2 is associated with increased oxidative and nitrosative stress, leading to amplification of cytokine production, and the NF-κB factor is readily activated in oxidative environments (
The involvement of OS in the progression and severity of COVID-19 has not been fully demonstrated; however, a study showed the increase of high-sensitivity CRP (hs-CRP), a marker of OS, in patients that died after COVID-19 disease (
The pathophysiology of MIS-C is not exactly known, and OS could play an important role: first, OS regulates the NF-κB, which in turn regulates the immune response and inflammation in several viral infections (
The pathophysiology of COVID-19 in adults includes endothelitis and lymphocytic endothelitis in organs such as the lung, heart, kidney and liver (
In SARS-CoV-2 infection, the binding of the receptor ACE2 with the virus leads to entry into the host cell and its subsequent replication and release. During the active phase of COVID-19, MIS-C patients were asymptomatic or with mild respiratory symptoms; however, three to four weeks after exposure to SARS-CoV-2, children develop a multi-organ disturbance. MIS-C is characterized by strong activation of T lymphocytes leading to the release of a cytokine storm and increased cytotoxic activity. Furthermore, T cells, together with monocytes and macrophages, promote oxidative stress by increasing reactive oxygen species, which alter macromolecules such as DNA, proteins and lipids. Additionally, the presence of autoantibodies that recognize endothelial cells, promoting damage and contributing to endothelial dysfunction and multisystem inflammation typical of MIS-C. Figure created with BioRender, ©
As mentioned previously, MIS-C has been associated due to its clinical characteristics with other inflammatory syndromes (TSS and KD), for which some common pathways and divergences are mentioned that may explain the participation of OS in MIS-C. It has been proposed that platelet count can help differentiate KD and MIS-C, since KD patients are characterized by normal/high platelet counts while MIS-C patients commonly present with lower platelet counts (
It is evident that in inflammatory syndromes there is an exacerbated and uncontrolled immune response, such as occurs with MIS-C; Therefore, prior knowledge of these syndromes can support the description of the pathophysiology in MIS-C, for example in the systemic inflammatory response syndrome (SIRS), there is an over-performance of cellular immune response, similar to what happens In patients with MIS-C, likewise, the participation of EO in SIRS is well known, reports report that in patients with a diagnosis of SIRS there are increases in lipoperoxidation, as well as decreased antioxidant capacity compared to patients without SIRS (
Similar to SIRS, there is evidence of OS involvement in KD, Some OS biomarkers, such as reactive oxygen metabolites (ROM), were increased in patients with KD naïve to treatment and favorably decreased in cases responding to treatment, in contrast to non-responding patients (
On the other hand, antioxidant markers are decreased in patients with KD in acute stages, such as the antioxidant power (
Although KD, SIRS, TSS, and MIS-C have differences, these diseases can provide a model for studying the pathogenesis of MIS-C, especially since KD, TSS, and SIRS are believed to be triggered by viral infections, sepsis, and can evolve to systemic inflammation and vasculitis (
The disorder MIS-C is a systemic hyper-inflammation developed by some children after SARS-CoV-2 infection. It shares clinical features and molecular mechanisms with other pathological entities, such as KD. Like KD, the exacerbated immune response in MIS-C could be associated with OS development
Further research is needed to support confirming whether OS plays an important role in the physiopathology of MIS-C, studies should be established focused on the search for new specific biomarkers on OS in these patients.
Conceptualization of the study, OG-M and SS-F. Literature search, GV-R, IL-P, and JM-B. Writing—original draft preparation, GV-R, IL-P, OG-M, and SS-F. Writing—review and editing, JM-B, OG-M, and SS-F. All authors contributed to the article and approved the submitted version.
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.
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