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Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation.

ABSTRACT: During the current coronavirus disease 2019 (COVID-19) pandemic, a variety of mutations have accumulated in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, at the time of writing, four variants of concern are considered to be potentially hazardous to human society¹. The recently emerged B.1.617.2/Delta variant of concern is closely associated with the COVID-19 surge that occurred in India in the spring of 2021 (ref. ²). However, the virological properties of B.1.617.2/Delta remain unclear. Here we show that the B.1.617.2/Delta variant is highly fusogenic and notably more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates cleavage of the spike protein and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity compared with its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity.

SUBMITTER: Saito A

PROVIDER: S-EPMC8828475 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation.

Saito Akatsuki A Irie Takashi T Suzuki Rigel R Maemura Tadashi T Nasser Hesham H Uriu Keiya K Kosugi Yusuke Y Shirakawa Kotaro K Sadamasu Kenji K Kimura Izumi I Ito Jumpei J Wu Jiaqi J Iwatsuki-Horimoto Kiyoko K Ito Mutsumi M Yamayoshi Seiya S Loeber Samantha S Tsuda Masumi M Wang Lei L Ozono Seiya S Butlertanaka Erika P EP Tanaka Yuri L YL Shimizu Ryo R Shimizu Kenta K Yoshimatsu Kumiko K Kawabata Ryoko R Sakaguchi Takemasa T Tokunaga Kenzo K Yoshida Isao I Asakura Hiroyuki H Nagashima Mami M Kazuma Yasuhiro Y Nomura Ryosuke R Horisawa Yoshihito Y Yoshimura Kazuhisa K Takaori-Kondo Akifumi A Imai Masaki M Tanaka Shinya S Nakagawa So S Ikeda Terumasa T Fukuhara Takasuke T Kawaoka Yoshihiro Y Sato Kei K

Nature 20211125 7896

During the current coronavirus disease 2019 (COVID-19) pandemic, a variety of mutations have accumulated in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, at the time of writing, four variants of concern are considered to be potentially hazardous to human society<sup>1</sup>. The recently emerged B.1.617.2/Delta variant of concern is closely associated with the COVID-19 surge that occurred in India in the spring of 2021 (ref. <sup>2</sup>). However, the vir ...[more]

PMID: 34823256

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Project description:SARS-CoV-2 infects both the upper and lower respiratory tracts, which are characterized by different temperatures (33°C and 37°C, respectively). In addition, fever is a common COVID-19 symptom. SARS-CoV-2 has been shown to replicate more efficiently at low temperatures, but the effect of temperature on different viral proteins remains poorly understood. Here, we investigate how temperature affects the SARS-CoV-2 spike function and evolution. We first observed that increasing temperature from 33°C to 37°C or 39°C increased spike-mediated cell-cell fusion. We then experimentally evolved a recombinant vesicular stomatitis virus expressing the SARS-CoV-2 spike at these different temperatures. We found that spike-mediated cell-cell fusion was maintained during evolution at 39°C but was lost in a high proportion of viruses that evolved at 33°C or 37°C. Consistently, sequencing of the spikes evolved at 33°C or 37°C revealed the accumulation of mutations around the furin cleavage site, a region that determines cell-cell fusion, whereas this did not occur in spikes evolved at 39°C. Finally, using site-directed mutagenesis, we found that disruption of the furin cleavage site had a temperature-dependent effect on spike-induced cell-cell fusion and viral fitness. Our results suggest that variations in body temperature may affect the activity and diversification of the SARS-CoV-2 spike.ImportanceWhen it infects humans, SARS-CoV-2 is exposed to different temperatures (e.g., replication site and fever). Temperature has been shown to strongly impact SARS-CoV-2 replication, but how it affects the activity and evolution of the spike protein remains poorly understood. Here, we first show that high temperatures increase the SARS-CoV-2 spike fusogenicity. Then, we demonstrate that the evolution of the spike activity and variants depends on temperature. Finally, we show that the functional effect of specific spike mutations is temperature-dependent. Overall, our results suggest that temperature may be a factor influencing the activity and adaptation of the SARS-CoV-2 spike in vivo, which will help understanding viral tropism, pathogenesis, and evolution.

Dataset Information

Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation.

Publications

Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation.

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