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Hypothesis Article: Free SARS-CoV-2 spike protein S1 particles may act as a factor of COVID-19 pathogenesis
  • Andrey Letarov,
  • Vladislav Babenko,
  • Eugene Kulikov
Andrey Letarov
Federal Research Center "Fundamentals of Biotechnology", Russian Academy of Sciences
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Vladislav Babenko
FSBI Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical Biological Agency of Russia
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Eugene Kulikov
Winogradsky Institute of Microbiology, FRC "Fundamentals of Biotechnology", Russian Academy of Sciences
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Abstract

The disbalance of the renin-angiotensin system was suggested to play an important role in the pathogenesis of the COVID-19 disease. Previously it has been shown that ACE2 expression in downregulated in the murine model in response to SARS-CoV infection and may be also induced by the recombinant spike protein alone. In case of natural infection the circulation of a soluble form of S protein is unlikely, however upon the transition into the fusion conformation, the S1 particles carrying the receptor-binding domains get separated from the membrane-bound moiety S2. The fate of the S1 particles liberated due to spontaneous firing of the S protein trimers exposed on the virion and on the external surface of the infected cells was never investigated.  We hypothesize that the soluble SARS-CoV-2 spike protein S1 subunits shed from the infected cells and from the virions in vivo may bind to the ACE2 receptor and trigger ACE2 downregulation.  Decreased ACE2 activity on the background of the constant or increased ACE activity in the lungs may lead to the prevalence of angiotensin II effects over angiotensin(1-7) connected to increased thrombosis, inflammation and pulmonary damage. This mechanism also suggests the link between the lowered S1 particles shedding reported for the S protein with D614G  mutation and the lack of  the elevated severity of the COVID-19 caused by the corresponding lineage of SARS-CoV-2 virus, despite the fact that is features increased infectivity and develops higher viral loads in vivo.