【摘 要】
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Host cellular receptors play key roles in the determination of virus tropism and pathogenesis.However,little is known about SARS-CoV-2 host receptors with the exception of ACE2.Furthermore,ACE2 alone cannot explain the multi-organ tropism of SARS-CoV-2 no
【机 构】
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The Fifth People’s Hospital of Shanghai,the Shanghai Key Laboratory of Medical Epigenetics,the Inter
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Host cellular receptors play key roles in the determination of virus tropism and pathogenesis.However,little is known about SARS-CoV-2 host receptors with the exception of ACE2.Furthermore,ACE2 alone cannot explain the multi-organ tropism of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV,suggesting the involvement of other receptor(s).Here,we performed genomic receptor profiling to screen 5054 human membrane proteins individually for interaction with the SARS-CoV-2 capsid spike (S) protein.Twelve proteins,including ACE2,ASGR1,and KREMEN1,were identified with diverse S-binding affinities and patterns.ASGR1 or KREMEN1 is sufficient for the entry of SARS-CoV-2 but not SARS-CoV in vitro and in vivo.SARS-CoV-2 utilizes distinct ACE2/ASGR1/KREMEN1 (ASK) receptor combinations to enter different cell types,and the expression of ASK together displays a markedly stronger correlation with Virus susceptibility than that of any individual receptor at both the cell and tissue levels.The cocktail of ASK-related neutralizing antibodies provides the most substantial blockage of SARS-CoV-2 infection in human lung organoids when compared to individual antibodies.Our study revealed an interacting host receptome of SARS-CoV-2,and identified ASGR1 and KREMEN1 as alternative functional receptors that play essential roles in ACE2-independent virus entry,providing insight into SARS-CoV-2 tropism and pathogenesis,as well as a community resource and potential therapeutic strategies for further COVID-19 investigations.
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