Angiotensin-Converting Enzyme 2 Potentiates SARS-CoV-2 Infection by Antagonizing Type I Interferon Induction and Its Down-Stream Signaling Pathway

Angiotensin-Converting Enzyme 2 Potentiates SARS-CoV-2 Infection by Antagonizing Type I Interferon Induction and Its Down-Stream Signaling Pathway

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ABSTRACT The innate interferon (IFN) response constitutes the first line of host defense against viral infections.It has been shown that IFN-I/III treatment could effectively contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro.However, how SARS-CoV-2 survives through the innate antiviral mechanism remains to be explored.Our study uncovered that human angiotensin-converting enzyme 2 (ACE2), identified as a primary receptor for SARS-CoV-2 entry, can disturb the IFN-I signaling pathway during SARS-CoV-2 infection in human lung cells.

We identified that ACE2 was significantly upregulated by SARS-CoV-2 and Sendai virus (SeV) infection, and exogenous expression of ACE2 suppressed IFN-I production in a dose-dependent manner.Mechanistically, ACE2 disrupted poly (I:C)-mediated inhibition of SARS-CoV2 replication by antagonizing IFN-I production by blocking IRF3 phosphorylation and nuclear translocation.Moreover, ACE2 quenched the IFN-mediated antiviral immune response by degrading endogenous STAT2 protein, inhibiting STAT2 phosphorylation and nuclear translocation.Interestingly, IFN-inducible short ACE2 (dACE2 or weleda skin food 75ml best price MIRb-ACE2) can also be induced by virus infection and inhibits the IFN signaling.

Thus, our findings provide mechanistic insight into the distinctive role of ACE2 in promoting SARS-CoV-2 infection and enlighten us that the development of interventional strategies might be further optimized to interrupt ACE2-mediated suppression of IFN-I and its signaling pathway.IMPORTANCE Efficient antiviral immune responses against SARS-CoV-2 infection play a key role in controlling the coronavirus diseases 2019 (COVID-19) caused by this virus.Although SARS-CoV-2 has developed strategies to counteract the IFN-I signaling through the virus-derived proteins, our knowledge of how SARS-CoV-2 survives through the innate antiviral mechanism remains poor.We herein chainsaw file discovered the distinctive role of ACE2 as a restraining factor of the IFN-I signaling in facilitating SARS-CoV-2 infection in human lung cells.

Both full-length ACE2 and truncated dACE2 can antagonize IFN-mediated antiviral response.These findings are key to understanding the counteraction between SARS-CoV-2 pathogenicity and the host antiviral defenses.