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The interferon-stimulated exosomal hACE2 potently inhibits SARS-CoV-2 replication through competitively blocking the virus entry.

ABSTRACT: Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/β treatment. In particular, exosomal hACE2 can specifically block the cell entry of SARS-CoV-2, subsequently inhibit the replication of SARS-CoV-2 in vitro and ex vivo. Our findings have indicated that IFN is able to upregulate a viral receptor on the exosomes which competitively block the virus entry, exhibiting a potential antiviral strategy.

SUBMITTER: Zhang J

PROVIDER: S-EPMC8113286 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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The interferon-stimulated exosomal hACE2 potently inhibits SARS-CoV-2 replication through competitively blocking the virus entry.

Zhang Junsong J Huang Feng F Xia Baijin B Yuan Yaochang Y Yu Fei F Wang Guanwen G Chen Qianyu Q Wang Qian Q Li Yuzhuang Y Li Rong R Song Zheng Z Pan Ting T Chen Jingliang J Lu Gen G Zhang Hui H

Signal transduction and targeted therapy 20210512 1

Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/β tre ...[more]

PMID: 33980808

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Project description:Many viruses activate cellular autophagy in infected cells to facilitate their replication. Recently, we identified an interferon (IFN)-stimulated gene (ISG) Tudor domain containing 7 (TDRD7), which inhibits viral replication by blocking autophagy pathway. Here, we present a molecular mechanism for TDRD7 action and its relative contribution to protection against viral pathogenesis. TDRD7 inhibited the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a kinase required for initiating autophagy. Mechanistically, TDRD7 interacted directly with AMPK in the cytosolic compartment. Domain-mapping analyses revealed C-terminal Tudor domain of TDRD7 interacted with auto-inhibitory domain of AMPK. Deletion of Tudor domains abolished anti-AMPK and antiviral activities of TDRD7. We evaluated physiological relevance of TDRD7 function against viral replication using newly engineered TDRD7 knockout mice and the derived primary cells. TDRD7 knockout primary cells displayed increased AMPK activation, which led to a higher viral load. Subsequently, TDRD7 knockout mice showed enhanced susceptibility upon intranasal Sendai virus infection. Therefore, our study revealed a new antiviral function of IFN, mediated by TDRD7-AMPK, inhibiting viral replication and pathogenesis. IMPORTANCE Virus infection triggers induction of interferon (IFN)-stimulated genes (ISGs), which ironically inhibit viruses themselves. We identified Tudor domain-containing 7 (TDRD7) as a novel antiviral ISG, which inhibits viral replication by interfering with autophagy pathway. Here, we present a molecular basis for autophagy inhibitory function of TDRD7. TDRD7 interacted with adenosine monophosphate (AMP)-activated protein kinase (AMPK), the kinase that initiates autophagy, to inhibit its activation. We identified domains required for the interaction; deleting AMPK-interacting domain blocked antiAMPK and antiviral activities of TDRD7. We used primary cells and mice to evaluate the TDRD7-AMPK antiviral pathway. TDRD7-deficient primary mouse cells exhibited enhanced AMPK activation and viral replication. Finally, TDRD7 knockout mice showed increased susceptibility to respiratory virus infection. Therefore, our study revealed a new antiviral pathway of IFN and its contribution to host response. Our results have therapeutic potential; a TDRD7-derived peptide may be an effective AMPK inhibitor with application as antiviral agent.

Dataset Information

The interferon-stimulated exosomal hACE2 potently inhibits SARS-CoV-2 replication through competitively blocking the virus entry.

Publications

The interferon-stimulated exosomal hACE2 potently inhibits SARS-CoV-2 replication through competitively blocking the virus entry.

Similar Datasets

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