Contribution of Coronavirus-Specific Immunoglobulin G Responses to Complement Overactivation in Patients with Severe Coronavirus Disease 2019

Abstract 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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of infectious diseases 2022-09, Vol.226 (5), p.766-777
Main Authors: Castanha, Priscila M S, Tuttle, Dylan J, Kitsios, Georgios D, Jacobs, Jana L, Braga-Neto, Ulisses, Duespohl, Matthew, Rathod, Sanjay, Marti, Michelle M, Wheeler, Sarah, Naqvi, Asma, Staines, Brittany, Mellors, John, Morris, Alison, McVerry, Bryan J, Shah, Faraaz, Schaefer, Caitlin, Macatangay, Bernard J C, Methe, Barbara, Fernandez, Christian A, Barratt-Boyes, Simon M, Burke, Donald, Marques, Ernesto T A
Format: Article
Language:English
Subjects:
Antigen-antibody complexes
Classical pathway
Common cold
Complement activation
Complement component C1q
Coronaviruses
COVID-19
Immunoglobulin G
Immunoglobulins
Major
Plasma levels
Severe acute respiratory syndrome coronavirus 2
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract 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. Our findings reveal that complement overactivation is mediated by the classical pathway in response to increased levels of circulating immune complexes and support the notion that an overexuberant immunoglobulin G response against severe acute respiratory syndrome coronavirus 2 and seasonal coronaviruses contributes to coronavirus disease 2019 severity.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiac091