Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

Sun, Shihui; Gu, Huiying; Cao, Lei; Chen, Qi; Ye, Qing; Guan, Yang; Li, Rui-Ting; Fan, Hang; Deng, Yong-Qiang; Song, Xiaopeng; Qi, Yini; Li, Min; Lei, Jun; Feng, Rui; Guo, Yan; Zhu, Na; Qin, Si; Wang, Lei; Zhang, Yifei; Zhou, Chao; Zhao, Lingna; Chen, Yuehong; Shen, Meng‐Ru; Cui, Yu‐Jun; Yang, Xiao; Wang, Xinquan; Tan, Wenjie; Wang, Hui; Wang, Xiangxi; Qin, Cheng‐Feng

doi:10.1038/s41467-021-25903-x

Cited by 93 publications

(82 citation statements)

References 58 publications

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“…However, over the course of the pandemic, SARS-CoV-2 variants emerged that could infect mice. For example, variants harboring the spike mutation N501Y, which are relatively common in human patients (24.7%, CoV-GLUE-Viz, accessed on November 23 th , 2021), could infect mice ( Gu et al, 2020 ; Leist et al, 2020 ; Sun et al, 2021 ). If the progenitor of Omicron indeed evolved in a mouse species before the Omicron outbreak, we postulated that its spike protein likely adapted through increased binding affinity for mouse ACE2.…”

Section: Resultsmentioning

confidence: 99%

Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

Cai

Shan

Wang

et al. 2021

Journal of Genetics and Genomics

240

230

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The rapid accumulation of mutations in the SARS-CoV-2 Omicron variant that enabled its outbreak raises questions as to whether its proximal origin occurred in humans or another mammalian host. Here, we identified 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage. We found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting a possibility of host-jumping. The molecular spectrum of mutations ( i.e. , the relative frequency of the 12 types of base substitutions) acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients, but resembled the spectra associated with virus evolution in a mouse cellular environment. Furthermore, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.

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Section: Resultsmentioning

confidence: 99%

Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

Cai

Shan

Wang

et al. 2021

Journal of Genetics and Genomics

240

230

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“…Coincidentally, two recent works showed that mouse-adapted SARS-CoV-2 strains MASCp6 and MASCp36, which harbored single-residue N501Y mutation and triple-residue K417N, Q493H and N501Y mutations, respectively, were capable of infecting wild-type mice. 12 , 15 The binding affinities of RBD (N501Y) and RBD (K417N, Q493H, and N501Y) to mACE2 were increased compared with the RBD of SARS-CoV-2 (G614). These works prompted us to investigate whether the natural SARS-CoV-2 variants, especially B.1.351 strain, might acquire the ability to directly infect the wild-type mice.…”

Section: Introductionmentioning

confidence: 99%

“…One is “adapting” virus to mice by serial passaging of virus in mice to enhance the binding affinity of the Spike to mACE2. 12 – 16 Another is “adapting” mice to SARS-CoV-2 viruses by introducing hACE2 in mice to facilitate the Spike-binding affinity. 17 – 23 However, the mouse-adapted SARS-CoV-2 strains often acquire adaptive mutations, some of which are even within RBD, which may restrict their transmission in humans.…”

Section: Introductionmentioning

confidence: 99%

Infection of wild-type mice by SARS-CoV-2 B.1.351 variant indicates a possible novel cross-species transmission route

Pan

Chen

et al. 2021

Sig Transduct Target Ther

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COVID-19 is identified as a zoonotic disease caused by SARS-CoV-2, which also can cross-transmit to many animals but not mice. Genetic modifications of SARS-CoV-2 or mice enable the mice susceptible to viral infection. Although neither is the natural situation, they are currently utilized to establish mouse infection models. Here we report a direct contact transmission of SARS-CoV-2 variant B.1.351 in wild-type mice. The SARS-CoV-2 (B.1.351) replicated efficiently and induced significant pathological changes in lungs and tracheas, accompanied by elevated proinflammatory cytokines in the lungs and sera. Mechanistically, the receptor-binding domain (RBD) of SARS-CoV-2 (B.1.351) spike protein turned to a high binding affinity to mouse angiotensin-converting enzyme 2 (mACE2), allowing the mice highly susceptible to SARS-CoV-2 (B.1.351) infection. Our work suggests that SARS-CoV-2 (B.1.351) expands the host range and therefore increases its transmission route without adapted mutation. As the wild house mice live with human populations quite closely, this possible transmission route could be potentially risky. In addition, because SARS-CoV-2 (B.1.351) is one of the major epidemic strains and the mACE2 in laboratory-used mice is naturally expressed and regulated, the SARS-CoV-2 (B.1.351)/mice could be a much convenient animal model system to study COVID-19 pathogenesis and evaluate antiviral inhibitors and vaccines.

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“…The SARS-CoV-2 primo-culture stocks used as B ( n = 1 viral strain) (EPI_ISL_4537783), Alpha ( n = 2) (EPI_ISL_4536454 and EPI_ISL_4536996), Beta ( n = 2) (EPI_ISL_4537125 and EPI_ISL_4537284), Gamma ( n = 1) (EPI_ISL_4536760), and A.27 ( n = 1) (EPI_ISL_4537460) was produced in Vero E6 cells. The supernatant were quantified with viral RNA levels and titrated by lysis plaque assay ( Gordon et al., 2020 ), aliquoted, and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

“…SARS-CoV-2 was titrated by a lysis-plaque assay as previously described ( Gordon et al., 2020 ). Briefly, Vero E6 cells were seeded onto a 12-well plate at a density of 100,000 in DMEM with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Earlier In Vitro Viral Production With SARS-CoV-2 Alpha Than With Beta, Gamma, B, or A.27 Variants

Lebourgeois

Chenane

Houhou‐Fidouh

et al. 2021

Front. Cell. Infect. Microbiol.

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Since its emergence in China at the end of 2019, SARS-CoV-2 has rapidly spread across the world to become a global public health emergency. Since then, the pandemic has evolved with the large worldwide emergence of new variants, such as the Alpha (B.1.1.7 variant), Beta (B.1.351 variant), and Gamma (P.1 variant), and some other under investigation such as the A.27 in France. Many studies are focusing on antibody neutralisation changes according to the spike mutations, but to date, little is known regarding their respective replication capacities. In this work, we demonstrate that the Alpha variant provides an earlier replication in vitro, on Vero E6 and A549 cells, than Beta, Gamma, A.27, and historical lineages. This earlier replication was associated with higher infectious titres in cell-culture supernatants, in line with the higher viral loads observed among Alpha-infected patients. Interestingly, Beta and Gamma variants presented similar kinetic and viral load than the other non-Alpha-tested variants.

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Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

Cited by 93 publications

References 58 publications

Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

Infection of wild-type mice by SARS-CoV-2 B.1.351 variant indicates a possible novel cross-species transmission route

Earlier In Vitro Viral Production With SARS-CoV-2 Alpha Than With Beta, Gamma, B, or A.27 Variants

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