Emerging roles of SARS-CoV-2 Spike-ACE2 in immune evasion and pathogenesis

ABSTRACT

Significance • The recent finding that the SARS-CoV-2 spike protein exploits ACE2 signaling to suppress immunological synapse assembly and CD8+ cytotoxic T lymphocyte-mediated killing highlights a potential role for the spike-ACE2 axis in the extrapulmonary manifestations of COVID-19. The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has caused an estimated 5 billion infections and 20 million deaths by respiratory failure. In addition to the respiratory disease, SARS-CoV-2 infection has been associated with many extrapulmonary complications not easily explainable by the respiratory infection. A recent study showed that the SARS-CoV-2 spike protein, which mediates cell entry by binding to the ACE2 receptor, signals through ACE2 to change host cell behavior. In CD8+ T cells, Spike-dependent ACE2-mediated signaling suppresses immunological synapse formation and impairs their killing ability, leading to immune escape of virus-infected cells. In this opinion article, we discuss the consequences of ACE2 signaling on the immune response and propose that it contributes to the extrapulmonary manifestations of COVID-19.