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《Nature，4月7日，SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion》

  • 来源专题：COVID-19科研动态监测
  • 编译者： zhangmin
  • 发布时间：2020-04-08

  • SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion

    Xinling Wang, Wei Xu, Gaowei Hu, Shuai Xia, Zhiping Sun, Zezhong Liu, Youhua Xie, Rong Zhang, Shibo Jiang & Lu Lu

    Cellular & Molecular Immunology (2020)

    COVID-19, the novel coronavirus disease caused by SARS-CoV-2 and outbroken at the end of 2019 in Wuhan, China,1 becomes a worldwide pandemic. SARS-CoV-2 belongs to the betacoronavirus genus and has 79.5% identity to SARS-CoV. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as its host entry receptor.2 The clinical manifestations of COVID-19 include pneumonia, diarrhea, dyspnea, and multiple organ failure. Interestingly, lymphocytopenia, as a diagnostic indicator, is common in COVID-19 patients. Xiong et al. found upregulation of apoptosis, autophagy, and p53 pathways in PBMC of COVID-19 patients.3 Some studies reported that lymphocytopenia might be related to mortality, especially in patients with low levels of CD3+, CD4+, and CD8+ T lymphocytes.

  • 原文来源：https://www.nature.com/articles/s41423-020-0424-9
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    • 来源专题：COVID-19科研动态监测
    • 编译者：xuwenwhlib
    • 发布时间：2020-06-14
    • The role of furin cleavage site in SARS-CoV-2 spike protein-mediated membrane fusion in the presence or absence of trypsin Shuai Xia, Qiaoshuai Lan, Shan Su, Xinling Wang, Wei Xu, Zezhong Liu, Yun Zhu, Qian Wang, Lu Lu & Shibo Jiang Signal Transduction and Targeted Therapy volume 5, Article number: 92 (2020) Cite this article The rapid spread of SARS-CoV-2 (also known as 2019-nCoV and HCoV-191), a novel lineage B betacoronavirus (βCoV), has caused a global pandemic of coronavirus disease (COVID-19). It has been speculated that RRAR, a unique furin-like cleavage site (FCS) in the spike protein (S), which is absent in other lineage B βCoVs, such as SARS-CoV, is responsible for its high infectivity and transmissibility.2 A coronavirus (CoV) infects the target cell by either cytoplasmic or endosomal membrane fusion. No matter what path it chooses, the final step of viral entry involves the release of RNA into the cytoplasm for replication. Therefore, the fusion capacity of the CoV-S is a leading indicator of infectivity of the corresponding virus. Consisting of S1 receptor-binding subunit and S2 fusion subunit, CoV-S needs to be primed through cleavage at S1/S2 site and S2′ site in order to mediate the membrane fusion (Fig. 1a). Previous studies have shown that an insertion of FCS consisting of multiple basic amino acids in the cleavage site of the haemagglutinin (HA) is associated with high virulence of influenza viruses.3 Coincidentally, phylogenetic analysis of SARS-CoV-2 identified an insertion of RRAR (FCS) at the S1/S2 site of SARS-CoV-2-S, which is absent in SARS-CoV and other SARS-related coronaviruses (SARSr-CoVs), particularly RaTG13, which has 96% identity of its genomic sequence to that of SARS-CoV-2 (Fig. 1b and Supplementary Fig. S1). Therefore, it has been speculated that this unique FCS may provide a gain-of-function, making SARS-CoV-2 easily enter into the host cell for infection, thus efficiently spreading throughout the human population, compared to other lineage B betacoronaviruses.2
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  • 《Nature，9月17日，Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-10-13
    • Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion Donald J. Benton, Antoni G. Wrobel, Pengqi Xu, Chloë Roustan, Stephen R. Martin, Peter B. Rosenthal, John J. Skehel & Steven J. Gamblin Nature (2020) Abstract SARS-CoV-2 infection is initiated by virus binding to ACE2 cell surface receptors1–4, followed by fusion of virus and cell membranes to release the virus genome into the cell. Both receptor binding and membrane fusion activities are mediated by the virus Spike glycoprotein, S5–7. As with other class I membrane fusion proteins, S is post-translationally cleaved, in this case by furin, into S1 and S2 components that remain associated following cleavage8–10. Fusion activation following receptor binding is proposed to involve the exposure of a second proteolytic site (S2’), cleavage of which is required for the fusion peptide release11,12. We have investigated the binding of ACE2 to the furin-cleaved form of SARS-CoV-2 S by cryoEM. We classify ten different molecular species including the unbound, closed spike trimer, the fully open ACE2-bound trimer, and dissociated monomeric S1 bound to ACE2. The ten structures describe ACE2 binding events which destabilise the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and un-shields the trimeric S2 core, priming fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of an S1 subdomain following ACE2 binding, that disrupts interactions with S2, notably involving Asp61413–15, leading to destabilisation of the structure of S2 proximal to the secondary (S2’) cleavage site.
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