Apolipoprotein E mediates cell resistance to influenza virus infection
Ping Gao, Miao Ji, Xinyuan Liu, Xiaotong Chen, Hongtao Liu, Shihua Li, Baoqian Jia, Chao Li, Lili Ren, Xin Zhao, Qihui Wang, Yuhai Bi, Xu Tan, Baidong Hou, Xuyu Zhou, Wenjie Tan, Tao Deng, Jianwei Wang, George F. Gao, Fuping Zhang
Abstract
Viruses exploit host cell machinery to support their replication. Defining the cellular proteins and processes required for a virus during infection is crucial to understanding the mechanisms of virally induced disease and designing host-directed therapeutics. Here, we perform a genome-wide CRISPR-Cas9–based screening in lung epithelial cells infected with the PR/8/NS1-GFP virus and use GFP hi cell as a unique screening marker to identify host factors that inhibit influenza A virus (IAV) infection. We discovered that APOE affects influenza virus infection both in vitro and in vivo. Cell deficiency in APOE conferred substantially increased susceptibility to IAV; mice deficient in APOE manifested more severe lung pathology, increased virus load, and decreased survival rate. Mechanistically, lack of cell-produced APOE results in impaired cell cholesterol homeostasis, enhancing influenza virus attachment. Thus, we identified a previously unrecognized role of APOE in restraining IAV infection.