Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 24, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ijms24033001
Keywords
neutrophils; SARS-CoV-2; cytokine storm; bacterial co-infection; LPS; Kawasaki disease; MIS-C; Toll-like receptors; NOD-like receptors; thrombosis
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Neutrophilia and the production of neutrophil extracellular traps (NETs) are markers of increased inflammation in severe COVID-19 and its autoimmune complications. The activation patterns of innate immunity in severe COVID-19 involve various receptors, including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) receptors. SARS-CoV-2 activates virus-associated innate receptors, but severe COVID-19 is characterized by additional activation of receptors responsive to bacterial antigens. Autoimmunity in COVID-19 complications is suggested to result from combined SARS-CoV-2-bacterial infections and synergistic inflammation.
Neutrophilia and the production of neutrophil extracellular traps (NETs) are two of many measures of increased inflammation in severe COVID-19 that also accompany its autoimmune complications, including coagulopathies, myocarditis and multisystem inflammatory syndrome in children (MIS-C). This paper integrates currently disparate measures of innate hyperactivation in severe COVID-19 and its autoimmune complications, and relates these to SARS-CoV-2 activation of innate immunity. Aggregated data include activation of Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) receptors, NOD leucine-rich repeat and pyrin-domain-containing receptors (NLRPs), retinoic acid-inducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA-5). SARS-CoV-2 mainly activates the virus-associated innate receptors TLR3, TLR7, TLR8, NLRP3, RIG-1 and MDA-5. Severe COVID-19, however, is characterized by additional activation of TLR1, TLR2, TLR4, TLR5, TLR6, NOD1 and NOD2, which are primarily responsive to bacterial antigens. The innate activation patterns in autoimmune coagulopathies, myocarditis and Kawasaki disease, or MIS-C, mimic those of severe COVID-19 rather than SARS-CoV-2 alone suggesting that autoimmunity follows combined SARS-CoV-2-bacterial infections. Viral and bacterial receptors are known to synergize to produce the increased inflammation required to support autoimmune disease pathology. Additional studies demonstrate that anti-bacterial antibodies are also required to account for known autoantigen targets in COVID-19 autoimmune complications.
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