Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice

• DOI: 10.1016/j.ebiom.2021.103381
• Publication Date: 2021-05-14T03:29:18Z
• Authors: Kun Huang; Yufei Zhang; Xianfeng Hui; Ya Zhao; Wenxiao Gong; Ting Wang; Shaoran Zhang; Yong Yang; Fei Deng; Qiang Zhang; Xi Chen; Ying Yang; Xiaomei Sun; Huanchun Chen; Yizhi J. Tao; Zhong Zou; Meilin Jin
• Keywords: Coronavirus; Infectivity; Knockout mouse

BackgroundAn ideal animal model to study SARS-coronavirus 2 (SARS-CoV-2) pathogenesis and evaluate therapies vaccines should reproduce SARS-CoV-2 infection recapitulate lung disease like those seen in humans. The angiotensin-converting enzyme (ACE2) is a functional receptor for SARS-CoV-2, but mice are resistant the because their ACE2 incompatible with receptor-binding domain (RBD) of spike protein .MethodsSARS-CoV-2 was passaged BALB/c obtain mouse-adapted virus strain. Complete genome deep sequencing different generations viruses performed characterize dynamics adaptive mutations SARS-CoV-2. Indirect immunofluorescence analysis Biolayer interferometry experiments determined binding affinity WBP-1 RBD mouse human ACE2. Finally, we tested whether TLR7/8 agonist Resiquimod (R848) could also inhibit replication model.FindingsThe strain showed increased infectivity led severe interstitial pneumonia. We characterized demonstrated that Q493K Q498H significantly its towards Additionally, tentatively found able protect against challenge. Therefore, this useful tool investigate COVID-19 develop new therapies.InterpretationWe first time enhanced interactive affinities mACE2. provides valuable evaluation novel antiviral vaccine strategies. This verified activity vitro vivo.FundingThis research funded by National Key Research Development Program China (2020YFC0845600) Emergency Science Technology Project Hubei Province (2020FCA046) Robert A. Welch Foundation (C-1565).