LAUSR

Since the outbreak of COVID-19 at the end of 2019, its causative agent SARS-CoV-2 has been spreading around the world for one and half a year. During the long global circulation of SARS-CoV-2, mutations in the viral genome gradually emerged and accumulated, which have led to the emergence of Variants of Concerns (VOC). The mutation linage B.1.351 (also termed as 501Y.V2 or Beta variant by WHO) was announced in December 2020 and rapidly became the predominant lineage in South Africa. The B.1.351 is characterized by eight mutations in S protein, including K417N, E484K and N501Y in RBD (Tegally et al. 2021). The N501Y and E484K mutations have been demonstrated reducing neutralizing titer of antibodies, vaccine-induced and SARS-CoV-2-infected sera in vitro, which raised concerns of current vaccine efficacy against the mutation lineages (Li et al. 2021; Wang et al. 2021). Previously, we have demonstrated the ACE2 humanized mice (hACE2), whose ACE2 (mACE2) genes were replaced with the human ACE2 by using CRISPR/Cas9 knock-in technology, are highly susceptive to SARS-CoV-2 isolated in early 2020 (Singh et al. 2020; Sun et al. 2020). Thereafter, the hACE2 mice model has been widely used to investigate the pathogenic mechanism and evaluate antivirals against SARS-CoV-2 (Lv et al. 2020; Ye et al. 2020; Zhu et al. 2020). However, the infectivity and pathogenicity of B.1.351 variant remains not determined. Herein, we characterized the replication dynamic and clinical outcome of B.1.351 variant in hACE2 mice with the same protocol as previously described. Accordingly, two groups of 12-month-old female hACE2 mice were intranasally challenged with the B.1.351 variant at a dose of 1.2 9 10 plaque forming unit (pfu) per mouse for daily monitoring (n = 8) and tissue collection (n = 12), respectively (Fig. 1A). The 501Y.V2-infected mice began to show ruffled fur and reduced activity on 3 days post infection. Meanwhile, B.1.351 variant infection caused significant weight loss, and the average weight loss reached * 13% on 3 days post infection (Fig. 1B). Then the mice began to recover and no death occurred during the seven-day observation period. These results indicate that the B.1.351 variant is pathogenic for the hACE2 mice, and leads more severe clinical symptoms than the prototype strain (IME-BJ05), which led only * 10% weight loss and no obvious clinical symptoms (Sun et al. 2020). SARS-CoV-2 subgenomic RNA (sgRNA) quantitation was further performed for detecting the viral loads in the main tissues and serum of mice on day 1, 3, 5 and 7 post infection. Results showed that high level of SARS-CoV-2 sgRNA was detected in the lungs and tracheas from B.1.351-infected mice (Fig. 1C). An obvious sgRNA increasing trend was observed in lung tissues and tracheas during 1–3 days post infection, and then the sgRNA loads Qi Chen, Xing-Yao Huang, Ying Tian, Changfa Fan, and Mengxu Sun these authors are contributed equally.