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SARS-CoV-2 Immune Complex-Mediated Neutrophil Activation.
Kiana C Allen1,2, Seth Warner1,2, Heather L Teague1,2
1Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.
Open Forum Infectious Diseases
|April 21, 2025
Summary
COVID-19 severity is linked to SARS-CoV-2 antibody levels and neutrophil activation. Antigen-antibody complexes, particularly IgA, drive NETosis, a process that can be inhibited by spleen tyrosine kinase blockers.
Area of Science:
- Immunology
- Virology
- Critical Care Medicine
Background:
- Understanding critical illness pathogenesis is key for developing therapies.
- COVID-19, caused by SARS-CoV-2, presents a significant global health challenge requiring deeper insights into its mechanisms.
Purpose of the Study:
- To investigate the association between SARS-CoV-2-specific antibody levels, neutrophil activation, and COVID-19 disease severity.
- To explore the link between adaptive and innate immune responses in severe COVID-19.
- To elucidate the role of SARS-CoV-2 immune complexes in neutrophil extracellular trap formation (NETosis).
Main Methods:
- Analysis of SARS-CoV-2-specific antibody levels and neutrophil activation markers in hospitalized COVID-19 patients.
- In vitro assays to assess the capacity of SARS-CoV-2 antigen-antibody immune complexes to stimulate NETosis.
- Evaluation of the differential roles of IgA and IgG immune complexes in NETosis.
- Assessment of spleen tyrosine kinase inhibition on NETosis.
Main Results:
- Higher SARS-CoV-2-specific antibody levels and neutrophil activation markers correlate with increased COVID-19 disease severity.
- A significant association exists between antibody levels and markers of neutrophil degranulation and NETosis.
- SARS-CoV-2 antigen-antibody immune complexes directly stimulate NETosis in vitro.
- IgA immune complexes show a stronger association with NETosis compared to IgG complexes.
- Spleen tyrosine kinase inhibition effectively ameliorates SARS-CoV-2-induced NETosis.
Conclusions:
- SARS-CoV-2-specific antibodies and neutrophil activation are key indicators of disease severity in hospitalized patients.
- The adaptive immune response, via antibody-immune complexes, directly influences innate immune cell behavior, specifically promoting NETosis.
- Targeting spleen tyrosine kinase may offer a therapeutic strategy to mitigate detrimental NETosis in severe COVID-19.
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