Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant

Li, Baisheng; Deng, Aiping; Li, Kuibiao; Hu, Yao; Li, Zhencui; Xiong, Qianling; Liu, Zhe; Guo, Qianfang; Zou, Lirong; Zhang, Huan; Zhang, Meng; Ouyang, Fangzhu; Su, Juan; Su, Wenzhe; Xu, Jing; Lin, Hung-Ching; Sun, Jing; Peng, Jinju; Jiang, Huimin; Zhou, Pingping; Hu, Ting; Luo, Min; Zhang, Yingtao; Zheng, Huanying; Xiao, Jianpeng; Liu, Tao; Che, Rongfei; Zeng, Hanri; Zheng, Zhong; Huang, Yushi; Jian-xiang, YU; Liu, Yi; Wu, Jie; Chen, Jing-diao; Zhong, Huan; Deng, Xiaoling; Kang, Min; Pybus, Oliver G.; Hall, Matthew; Lythgoe, Katrina A.; Li, Yan; Yuan, Jun; He, Jianfeng; Lu, Jing

doi:10.1101/2021.07.07.21260122

Cited by 233 publications

(175 citation statements)

References 35 publications

(27 reference statements)

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“…Lastly, our unexpected finding of improved RNA packaging and luciferase induction by mutations within the N protein point to a previously unknown strategy for coronaviruses to evolve improved viral fitness. Although the mechanism for this improvement remains unclear, this finding is consistent with recent reports that the Delta variant (containing N:R203M) generates 1000-fold higher levels of RNA within patients ( 26 ). Our results point to a new and unanticipated mechanism that could explain why the SARS-CoV-2 Delta variant demonstrates improved viral fitness.…”

Section: Main Textsupporting

confidence: 91%

Rapid assessment of SARS-CoV-2 evolved variants using virus-like particles

Syed

Taha

Khalid

et al. 2021

Preprint

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Newly evolved SARS-CoV-2 variants are driving ongoing outbreaks of COVID-19 around the world. Efforts to determine why these viral variants have improved fitness are limited to mutations in the viral spike (S) protein and viral entry steps using non-SARS-CoV-2 viral particles engineered to display S. Here we show that SARS-CoV-2 virus-like particles can package and deliver exogenous transcripts, enabling analysis of mutations within all structural proteins and rapid dissection of multiple steps in the viral life cycle. Identification of an RNA packaging sequence was critical for engineered transcripts to assemble together with SARS-CoV-2 structural proteins S, nucleocapsid (N), membrane (M) and envelope (E) into non-replicative SARS-CoV-2 virus-like particles (SC2-VLPs) that deliver these transcripts to ACE2- and TMPRSS2-expressing cells. Using SC2-VLPs, we tested the effect of 30 individual mutations within the S and N proteins on particle assembly and entry. While S mutations unexpectedly did not affect these steps, SC2-VLPs bearing any one of four N mutations found universally in more-transmissible viral variants (P199L, S202R, R203M and R203K) showed increased particle production and up to 10-fold more reporter transcript expression in receiver cells. Our study provides a platform for rapid testing of viral variants outside a biosafety level 3 setting and identifies viral N mutations and viral particle assembly as mechanisms to explain the increased spread of current viral variants, including Delta (N:R203M).

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Section: Main Textsupporting

confidence: 91%

Rapid assessment of SARS-CoV-2 evolved variants using virus-like particles

Syed

Taha

Khalid

et al. 2021

Preprint

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“…S1). The high incidence of B.1.617.2 is consistent with recent studies showing that the B.1.617.2 variant has enhanced transmissibility, replication kinetics and viral loads in oropharyngeal and nose-throat swabs of infected individuals relative to the ancestral virus and other variants (37,44).…”

supporting

confidence: 88%

Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

McCallum

Walls

Sprouse

et al. 2021

Preprint

110

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Worldwide SARS-CoV-2 transmission leads to the recurrent emergence of variants, such as the recently described B.1.617.1 (kappa), B.1.617.2 (delta) and B.1.617.2+ (delta+). The B.1.617.2 (delta) variant of concern is causing a new wave of infections in many countries, mostly affecting unvaccinated individuals, and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing the impact of individual mutations on immune evasion. Mutations in the B.1.617.1 (kappa) and B.1.617.2 (delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including an unexpected remodeling of the B.1.617.2 (delta) N-terminal domain. The binding affinity of the B.1.617.1 (kappa) and B.1.617.2 (delta) receptor-binding domain for ACE2 is comparable to the ancestral virus whereas B.1.617.2+ (delta+) exhibits markedly reduced affinity. We describe a previously uncharacterized class of N-terminal domain-directed human neutralizing monoclonal antibodies cross-reacting with several variants of concern, revealing a possible target for vaccine development.

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“…This study shows that the SARS-CoV-2 B.1.351 variant can establish infection in WT mice, in line with previous findings (Montagutelli et al, 2021). Compared to hACE2-expressing transgenic mice that developed a severe clinical course and pathology upon SARS-CoV-2 infection, WT mice displayed a milder phenotype.…”

Section: Resultssupporting

confidence: 93%

“…The landscape of susceptibility species is also governed by S protein mutations, which can modulate the affinity to animal ACE2 (Garry, 2021). Notably, it has already been reported that new variants such as B.1.351 can infect SARS-CoV-2 resistant species like mice (Montagutelli et al, 2021). However, a complete in vivo susceptibility analysis has not yet been carried out.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 B.1.351 (beta) variant shows enhanced infectivity in K18-hACE2 transgenic mice and expanded tropism to wildtype mice compared to B.1 variant

Tarrés-Freixas

Trinité

Pons-Grífols

et al. 2021

Preprint

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SARS-CoV-2 variants display enhanced transmissibility and/or immune evasion and can be generated in humans or animals, like minks, thus generating new reservoirs. The continuous surveillance of animal susceptibility to new variants is necessary to predict pandemic evolution. In this study we demonstrate that, compared to the B.1 SARS-CoV-2 variant, K18-hACE2 transgenic mice challenged with the B.1.351 variant displayed a faster progression of infection. Furthermore, we also report that B.1.351 can establish infection in wildtype mice, while B.1 cannot. B.1.351-challenged wildtype mice showed a milder infection than transgenic mice, confirmed by detectable viral loads in oropharyngeal swabs and tissues, lung pathology, immunohistochemistry and serology. In silico models supported these findings by demonstrating that the Spike mutations in B.1.351 resulted in increased affinity for both human and murine ACE2 receptors. Overall, this study highlights the plasticity of SARS-CoV-2 animal susceptibility landscape, which may contribute to viral persistence and expansion.

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Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant

Cited by 233 publications

References 35 publications

Rapid assessment of SARS-CoV-2 evolved variants using virus-like particles

Rapid assessment of SARS-CoV-2 evolved variants using virus-like particles

Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

SARS-CoV-2 B.1.351 (beta) variant shows enhanced infectivity in K18-hACE2 transgenic mice and expanded tropism to wildtype mice compared to B.1 variant

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