Researchers from the Medical University of Vienna and the Medical University of Innsbruck found that SARS-CoV-2 hijacks three important host proteins that dampen the activity of the complement system, a key component of early antiviral immunity. This significantly impairs viral clearance, which may affect the course of both acute COVID-19 infections and post-COVID-19 sequelae. The study was recently published in the journal Microbes and emerging infections.
An early and effective immune response is crucial to resolve viral infections and prevent post-infectious complications. The complement system, a fundamental element of antiviral immunity, is a cascade of proteins found in the bloodstream and in mucous membranes, such as the respiratory tract. Activated through three different pathways, complement facilitates the elimination of viral particles by directly inducing their destruction (lysis). To prevent external damage to host cells, complement is rapidly inactivated by a set of host molecules called complement regulatory proteins. The new study led by Anna Ohradanova-Repic and colleagues from the Center for Pathophysiology, Infectology and Immunology at the Medical University of Vienna in collaboration with Heribert Stoiber’s team at the Institute of Virology at the Medical University of Innsbruck shows that SARS-CoV – 2 sequesters three of these regulatory proteins, CD55, CD59, and Factor H, and is therefore successfully protected from complement-mediated lysis.
Sequestration of host proteins for effective complement resistance
By propagating SARS-CoV-2 in human cells, the researchers found that the virus particles acquire the cellular proteins CD55 and CD59. Additional experiments showed that SARS-CoV-2 also binds to factor H, another complement regulatory protein found primarily in the bloodstream. Confronting the virus particles with active complement revealed that they are partially resistant to complement-mediated lysis. By removing CD55, CD59, and factor H from the surface of the virus or inhibiting their biological functions, the researchers were able to successfully restore complement-mediated clearance of SARS-CoV-2.
“By sequestering these three proteins, SARS-CoV-2 can evade all three complement pathways, resulting in reduced or delayed viral clearance by the infected host,” explains Anna Ohradanova-Repic, leader of the study. Because complement is closely linked to other components of the immune system, this not only affects virus clearance but can also cause significant inflammation, a central feature of both severe COVID-19 and long COVID.
“Uncovering immune evasion mechanisms that allow the virus to remain within the host longer deepens our understanding of the acute and long-term impacts of SARS-CoV-2 infection,” says first author Laura Gebetsberger.