Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes  

作　　者：Xinyi Yang Xu Zheng Yuqi Zhu Xiaying Zhao Jun Liu Jiangna Xun Songhua Yuan Jun Chen Hanyu Pan Jinlong Yang Jing Wang Zhimin Liang Xiaoting Shen Yue Liang Qinru Lin Huitong Liang Min Li Fei Peng Daru Lu Jianqing Xu Hongzhou Lu Shibo Jiang Ping Zhao Huanzhang Zhu 

机构地区：[1]State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology,Ministry of Education,Institute of Genetics,School of Life Sciences,Yiwu Research Institute,Fudan University,Shanghai,China [2]Department of Microbiology,Faculty of Naval Medicine,Naval Medical University,Shanghai 200433,China [3]Scientific Research Center,Shanghai Public Health Clinical Center,Fudan University,Shanghai,China [4]Department of Infectious Diseases and Immunology,Shanghai Public Health Clinical Center,Fudan University,Shanghai,China [5]Changzheng Hospital,Naval Medical University,Shanghai,China [6]Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS),Shanghai Institute of Infectious Disease and Biosecurity,School of Basic Medical Sciences,Fudan University,Shanghai,China [7]Department of Infectious Diseases and Nursing Research Institution,National Clinical Research Center for Infectious Diseases,The Third People’s Hospital of Shenzhen,Shenzhen,Guangdong,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第3期1199-1208,共10页信号转导与靶向治疗（英文）

基　　金：supported by the National Natural Science Foundation of China(82041001,31771484,81761128020,92169112)。

摘　　要：Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)causes multi-organ damage,which includes hepatic dysfunction,as observed in over 50%of COVID-19 patients.Angiotensin I converting enzyme(peptidyl-dipeptidase A)2(ACE2)is the primary receptor for SARS-CoV-2 entry into host cells,and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2,but at extremely low levels.Consequently,we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into cells.To address this question,we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1(ASGR1)promoted SARS-CoV-2 pseudovirus infection of HeLa cells.In Huh-7 cells,simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection.In the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells,both of which barely expressed ACE2,SARSCoV-2 pseudovirus could successfully establish an infection.However,after treatment with ASGR1 antibody or siRNA targeting ASGR1,the infection rate significantly dropped,suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent mechanism.We confirmed that ASGR1 could interact with Spike protein,which depends on receptor binding domain(RBD)and N-terminal domain(NTD).Finally,we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal cells.After inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA,the infection efficiency of the live virus decreased significantly.Collectively,these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.

关 键 词：ACE2 INFECTION GLYCOPROTEIN 

分 类 号：R373[医药卫生—病原生物学]