J Infect Dis . IgG response to SARS-CoV-2 and seasonal coronaviruses contributes to complement overactivation in severe COVID-19 patients

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J Infect Dis


. 2022 Mar 10;jiac091.
doi: 10.1093/infdis/jiac091. Online ahead of print.
IgG response to SARS-CoV-2 and seasonal coronaviruses contributes to complement overactivation in severe COVID-19 patients


Priscila M S Castanha ¹ , Dylan J Tuttle ¹ , Georgios D Kitsios ^{2 3 4} , Jana L Jacobs ⁵ , Ulisses Braga-Neto ⁶ , Matthew Duespohl ¹ , Sanjay Rathod ⁷ , Michelle M Marti ¹ , Sarah Wheeler ⁸ , Asma Naqvi ⁵ , Brittany Staines ⁵ , John Mellors ⁵ , Alison Morris ^{2 4} , Bryan J McVerry ^{2 3 4} , Faraaz Shah ³ , Caitlin Schaefer ² , Bernard J C Macatangay ⁵ , Barbara Methe ^{2 4} , Christian A Fernandez ⁷ , Simon M Barratt-Boyes ^{1 9} , Donald Burke ¹⁰ , Ernesto T A Marques ¹



Affiliations

• PMID: 35267024
• DOI: 10.1093/infdis/jiac091

Abstract

Background: Excessive complement activation has been implicated in the pathogenesis of COVID-19, but the mechanisms leading to this response remain unclear.
Methods: We measured plasma levels of key complement markers, SARS-CoV-2 RNA and antibodies against SARS-CoV-2 and common cold coronaviruses (CCC) in hospitalized patients with COVID-19 of moderate (n=18) and critical severity (n=37), and healthy control subjects (n=10).
Results: We confirmed that complement activation is systemically increased in COVID-19 patients and is associated with a worse disease outcome. We showed that plasma levels of C1q and circulating immune complexes (CIC) were markedly increased in severe COVID-19 patients and correlated with higher IgG 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 CCC were strongly correlated with CIC levels, complement activation, and disease severity.
Conclusions: These findings indicate that early, non-neutralizing 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 COVID-19 patients.

Keywords: COVID-19; SARS-CoV-2; and antibodies; classical pathway; common cold coronaviruses; complement system.