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Contribution of Coronavirus-Specific Immunoglobulin G Responses to Complement Overactivation in Patients with Severe
Priscila M S Castanha1, Dylan J Tuttle1, Georgios D Kitsios2,3,4
1Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Insights
Excessive complement activation, linked to severe COVID-19, is driven by early IgG responses to SARS-CoV-2 and common cold viruses. This overactivation correlates with disease severity, highlighting a need for targeted therapies.
Area of Science:
- Immunology
- Virology
- Pathogenesis of Infectious Diseases
Background:
- Excessive complement activation is implicated in COVID-19 pathogenesis.
- The precise mechanisms driving this complement response remain unclear.
Purpose of the Study:
- To investigate the mechanisms of complement overactivation in COVID-19.
- To explore the role of antibody responses in complement activation and disease severity.
Main Methods:
- Measured plasma complement markers, SARS-CoV-2 RNA, and antibodies against SARS-CoV-2 and common cold coronaviruses (CCCs).
- Compared hospitalized COVID-19 patients (moderate and critical severity) with healthy controls.
- Analyzed correlations between complement markers, antibody titers, immune complexes, and disease severity.
Main Results:
- Complement activation was systemically increased in COVID-19 patients, correlating with worse outcomes.
- Elevated C1q and immune complexes in severe COVID-19 patients linked to higher IgG titers and disease severity.
- The classical complement pathway and early IgG responses to SARS-CoV-2 and CCCs were associated with complement overactivation and severity.
Conclusions:
- Early, potentially nonneutralizing IgG responses may drive complement overactivation in severe COVID-19.
- Therapeutic strategies targeting complement overactivation are urgently needed for COVID-19 patients.
Background:
Excessive complement activation has been implicated in the pathogenesis of coronavirus disease 2019 (COVID-19), but the mechanisms leading to this response remain unclear.
Methods:
We measured plasma levels of key complement markers, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies against SARS-CoV-2 and seasonal human common cold coronaviruses (CCCs) in hospitalized patients with COVID-19 of moderate (n = 18) and critical severity (n = 37) and in healthy controls (n = 10).
Results:
We confirmed that complement activation is systemically increased in patients with COVID-19 and is associated with a worse disease outcome. We showed that plasma levels of C1q and circulating immune complexes were markedly increased in patients with severe COVID-19 and correlated with higher immunoglobulin (Ig) G titers, greater complement activation, and higher disease severity score. Additional analyses showed that the classical pathway was the main arm responsible for augmented complement activation in severe patients. In addition, we demonstrated that a rapid IgG response to SARS-CoV-2 and an anamnestic IgG response to the nucleoprotein of the CCCs were strongly correlated with circulating immune complex levels, complement activation, and disease severity.
Conclusions:
These findings indicate that early, nonneutralizing IgG responses may play a key role in complement overactivation in severe COVID-19. Our work underscores the urgent need to develop therapeutic strategies to modify complement overactivation in patients with COVID-19.
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