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

Saito, Akatsuki; Irie, Takashi; Suzuki, Rigel; Maemura, Tadashi; Nasser, Hesham; Uriu, Keiya; Kosugi, Yusuke; Shirakawa, Kotaro; Sadamasu, Kenji; Kimura, Izumi; Ito, Jumpei; Wu, Jiaqi; Iwatsuki‐Horimoto, Kiyoko; Ito, Mutsumi; Yamayoshi, Seiya; Loeber, Samantha; Tsuda, Masumi; Wang, Lei; Ozono, Seiya; Butlertanaka, Erika P.; Tanaka, Yuri; Shimizu, Ryo; Shimizu, Kenta; Yoshimatsu, Kumiko; Kawabata, Ryoko; Sakaguchi, Takemasa; Tokunaga, Kenzo; Yoshida, Isao; Asakura, Hiroyuki; Nagashima, Mami; Kazuma, Yasuhiro; Nomura, Ryosuke; Horisawa, Yoshihito; Yoshimura, Kazuhisa; Takaori‐Kondo, Akifumi; Imai, Masaki; Chiba, Mika; Furihata, Hirotake; Hasebe, Haruyo; Kitazato, Kazuko; Kubo, Haruko; Misawa, Naoko; Morizako, Nanami; Noda, Kohei; Oide, Akiko; Suganami, Mai; Takahashi, Miyoko; Tsushima, Kana; Yokoyama, Miyabishara; Yuan, Yue; Tanaka, Shinya; Nakagawa, So; Ikeda, Terumasa; Fukuhara, Takasuke; Kawaoka, Yoshihiro; Sato, Kei

doi:10.1038/s41586-021-04266-9

Cited by 525 publications

(811 citation statements)

References 46 publications

Supporting

Mentioning

683

Contrasting

Unclassified

Order By: Relevance

“…Once a corona virus is bound to a human cell, disease severity is regulated by furin cleavage of the spike. After initial binding to the human ACE2 protein, Furin protease cleavage breaks the spike to facilitate cell wall fusion [6] and viral reproduction. The higher the furin-FCD HBond binding count, the more efficient the fusion at the molecular level, and ultimately, higher viral load on the host.…”

Section: Discussionmentioning

confidence: 99%

Simulation of the omicron variant of SARS-CoV-2 shows broad antibody escape, weakened ACE2 binding, and modest increase in furin binding

Jawaid

Baidya

Mahboubi-Ardakani

et al. 2021

Preprint

View full text Add to dashboard Cite

The recent emergence of the omicron variant of the SARS-CoV-2 virus with large numbers of mutations has raised concern about a potential new surge in infections. Here we use molecular dynamics to study the biophysics of the interface of the omicron spike protein binding to (i) the ACE2 receptor protein, (ii) antibodies from all known binding regions, and (iii) the furin binding domain. Our simulations suggest that while there is significant reduction of antibody binding strength corresponding to escape, the omicron spike pays a cost in terms of weaker receptor binding. The furin cleavage domain is the same or weaker binding than the alpha variant, suggesting less viral load and disease intensity than the extant delta variant.

show abstract

Section: Discussionmentioning

confidence: 99%

Simulation of the omicron variant of SARS-CoV-2 shows broad antibody escape, weakened ACE2 binding, and modest increase in furin binding

Jawaid

Baidya

Mahboubi-Ardakani

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…HOS-ACE2/TMPRSS2 cells (HOS cells stably expressing human ACE2 and TMPRESS2) 4,31 were maintained in Dulbecco's modified Eagle's medium (high glucose) (Wako, Cat# 044-29765) containing 10% foetal bovine serum (FBS) and 1% PS. VeroE6/TMPRSS2 cells [an African green monkey (Chlorocebus sabaeus) kidney cell line; JCRB1819] 32 were maintained in Dulbecco's modified Eagle's medium (low glucose) (Wako, Cat# 041-29775) containing 10% FBS, G418 (1 mg/ml; Nacalai Tesque, Cat# G8168-10ML) and 1% PS.…”

Section: Cell Culture For Live Virus Experimentsmentioning

confidence: 99%

“…Data on replication are limited however. Delta spike was previously shown to confer more efficient cell-cell fusion kinetics compared to Wuhan-1 2 , and syncytia formation has previously been associated with pathogenesis 3 . Moreover, changes in the polybasic cleavage site (PBCS) have been associated with pathogenicity.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to immune evasion, data on replication and cell entry efficiency are limited. Delta spike was previously shown to confer more efficient cell-cell fusion kinetics compared to Wuhan-1 3 , and syncytia formation has previously been associated with pathogenesis 4 . Omicron has three mutations in the furin cleavage site region (P681H, H655Y and N679K) and was initially predicted to be highly infectious 5 , fit and able to induce cell-cell fusion 6 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SARS-CoV-2 Omicron spike mediated immune escape and tropism shift

Meng

Ferreira

Abdullahi

et al. 2021

Preprint

Self Cite

104

View full text Add to dashboard Cite

The Omicron variant emerged in southern Africa in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that the Omicron spike confers very significant evasion of vaccine elicited neutralising antibodies that is more pronounced for ChAdOx-1 adenovirus vectored vaccine versus BNT162b2 mRNA vaccine. Indeed neutralisation of Omicron was not detectable for the majority of individuals who had received two doses of ChAdOx-1. Third dose mRNA vaccination rescues neutralisation in the short term. Despite three mutations predicted to favour spike S1/S2 cleavage, observed cleavage efficiency is lower than for wild type Wuhan-1 D614G and Delta. We demonstrate significantly lower infectivity of lung organoids and Calu-3 lung cells expressing endogenous levels of ACE2 and TMPRSS2 but similar infection as compared to Delta when using H1299 lung epithelial cells. Importantly, fusogenicity of the Omicron spike is impaired, leading to marked reduction in syncitia formation. These observations indicate that Omicron has gained immune evasion properties whilst possibly modulating properties associated with replication and pathogenicity.

show abstract

“…The B. 1.351 (Beta) VOC demonstrated the greatest magnitude of immune evasion from serum neutralizing antibodies 6,7 ,whereas B.1.617.2 (Delta) quickly outcompeted all other circulating isolates through acquisition of mutations that enhanced transmission and pathogenicity [10][11][12][13] and eroded neutralizing antibody responses 10 .…”

Section: Introductionmentioning

confidence: 99%

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

Cameroni

Saliba

Bowen

et al. 2021

Preprint

Self Cite

115

View full text Add to dashboard Cite

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab, S2X259 and S2H97, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

show abstract

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

Cited by 525 publications

References 46 publications

Simulation of the omicron variant of SARS-CoV-2 shows broad antibody escape, weakened ACE2 binding, and modest increase in furin binding

Simulation of the omicron variant of SARS-CoV-2 shows broad antibody escape, weakened ACE2 binding, and modest increase in furin binding

SARS-CoV-2 Omicron spike mediated immune escape and tropism shift

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

Contact Info

Product

Resources

About