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SARS-CoV-2 hijacks host CD55, CD59 and factor H to impair antibody-dependent complement-mediated lysis
Laura Gebetsberger1, Zahra Malekshahi2, Aron Teutsch2
1Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, Austria.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses host regulators CD55, CD59, and Factor H to evade complement-mediated killing. Blocking these proteins restores viral sensitivity to complement, revealing a novel immune escape strategy.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- The complement system is crucial for innate immunity against pathogens.
- Regulators of Complement Activation (RCAs) prevent excessive complement activity.
- SARS-CoV-2 pathogenesis involves complex host-pathogen interactions.
Purpose of the Study:
- To investigate how SARS-CoV-2 evades antibody-dependent complement-mediated lysis.
- To identify specific host factors utilized by SARS-CoV-2 for immune evasion.
- To explore therapeutic strategies targeting viral complement resistance.
Main Methods:
- Analysis of SARS-CoV-2 interaction with host RCAs (CD55, CD59, Factor H).
- Functional assays assessing complement-mediated lysis of SARS-CoV-2.
- Inhibition studies using blocking antibodies and recombinant proteins.
Main Results:
- SARS-CoV-2 utilizes host CD55, CD59, and Factor H to resist complement lysis.
- Blocking these RCAs restores viral sensitivity to complement-mediated killing.
- Complement-mediated virolysis requires classical pathway activation and virus-specific antibodies.
Conclusions:
- SARS-CoV-2 employs a sophisticated immune escape mechanism by hijacking host RCAs.
- Targeting these viral-host interactions could enhance complement-mediated viral clearance.
- Findings offer insights into COVID-19 immunopathology and potential therapeutic targets.
Abstract:
The complement system is a vital anti-microbial defence mechanism against circulating pathogens. Excessive complement activation can have deleterious outcomes for the host and is consequently tightly modulated by a set of membrane-associated and fluid-phase regulators of complement activation (RCAs). Here, we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks host cellular RCA members CD55 and CD59 and serum-derived Factor H (FH) to resist antibody-dependent complement-mediated lysis triggered by immunized human sera. Blockage of the biological functions of virion-associated CD55 and CD59 and competition of FH recruitment with functionally inactive recombinant FH-derived short consensus repeats SCR18-20 restore SARS-CoV-2 complement sensitivity in a synergistic manner. Moreover, complement-mediated virolysis is dependent on classical pathway activation and does not occur in the absence of virus-specific antibodies. Altogether, our findings present an intriguing immune escape mechanism that provides novel insights into the immunopathology observed in severe coronavirus disease 2019 (COVID-19).
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