A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Hoffmann, Markus; Kleine-Weber, Hannah; Pöhlmann, Stefan

doi:10.1016/j.molcel.2020.04.022

Cited by 1,785 publications

(2,299 citation statements)

References 45 publications

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“…The "PRRA" amino acid insertion at the S 1 /S 2 junction of SARS-CoV-2 spike was recently identi ed and was widely speculated to facilitate virus replication or expand virus tropism 23,24,26 . In this study, we carefully evaluated the importance of the reported S 1 /S 2 furin cleavage site in SARS-CoV-2 spike during SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

“…These residues are absent in the spike protein of SARS-CoV, SARS-CoV-related coronavirus (SARSr-CoV), and the closely related bat coronavirus RaTG13 25 . The additional furin-like cleavage site is widely postulated to facilitate virus entry and increase cell tropism, leading to e cient virus spread in the human population [23][24][25][26] . However, the physiological relevance of this furin-like motif in SARS-CoV-2 spike has not been functionally evaluated during infectious virus infection.…”

Section: Introductionmentioning

confidence: 99%

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Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

Chu

Huang

et al. 2020

Preprint

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SARS-CoV-2 has affected over 9 million patients with more than 460,000 deaths in about 6 months. Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells, which are not previously reported, may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we reported key host and viral determinants that were essential for efficient SARS-CoV-2 infection in the human lung. First, we identified heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Second, we demonstrated that while cell surface sialic acids significantly restricted SARS-CoV infection, SARS-CoV-2 could largely overcome sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissue explants. Third, we demonstrated that the inserted furin-like cleavage site in SARS-CoV-2 spike was required for efficient virus replication in human lung but not intestine tissues. Overall, these findings contributed to our understanding on efficient SARS-CoV-2 infection of human lungs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

Chu

Huang

et al. 2020

Preprint

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“…In our acutely exposed lung homogenates, we looked at ACE2, TMPRSS2, and Furin protein abundance and observed no association with cartridge exposures. The decrease in furin, spike glycoprotein cleaving protease, in male mice with the MCT exposure needs to be further investigated[59]. The exacerbated response in smokers and vapers may suggest that smoking/vaing with nicotine and α7nAChR with ACE2 may be involved [60].…”

Section: Resultsmentioning

confidence: 99%

Pulmonary toxicity and inflammatory response of e-cigarettes containing medium-chain triglyceride oil and vitamin E acetate: Implications in the pathogenesis of EVALI but independent of SARS-COV-2 COVID-19 related proteins

Muthumalage

Lucas

Wang

et al. 2020

Preprint

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Recently, there has been an outbreak associated with the use of e-cigarette or vaping products, associated lung injury (EVALI). The primary components of vaping products, vitamin E acetate (VEA) and medium-chain triglycerides (MCT) may be responsible for acute lung toxicity. Currently, little information is available on the physiological and biological effects of exposure to these products. We hypothesized that these e-cig cartridges and their constituents (VEA and MCT) induce pulmonary toxicity, mediated by oxidative damage and inflammatory responses, leading to acute lung injury. We studied the potential mechanisms of cartridge aerosol induced inflammatory response by evaluating the generation of reactive oxygen species by MCT, VEA, and cartridges, and their effects on the inflammatory state of pulmonary epithelium and immune cells both in vitro and in vivo. Cells exposed to these aerosols generated reactive oxygen species, caused cytotoxicity, induced epithelial barrier dysfunction, and elicited an inflammatory response. Using a murine model, the parameters of acute toxicity to aerosol inhalation were assessed. Infiltration of neutrophils and lymphocytes was accompanied by significant increases in IL-6, eotaxin, and G-CSF in the bronchoalveolar lavage fluid (BALF). In mouse plasma, eicosanoid inflammatory mediators, leukotrienes, were significantly increased. Plasma from e-cig users also showed increased levels of hydroxyeicosatetraenoic acid (HETEs) and various eicosanoids. Exposure to e-cig cartridge aerosols showed the most significant effects and toxicity compared to MCT and VEA. In addition, we determined at SARS-COV-2 related proteins and found no impact associated with aerosol exposures from these tested cartridges. Overall, this study demonstrates acute exposure to specific e-cig cartridges induces in vitro cytotoxicity, barrier dysfunction, and inflammation and in vivo mouse exposure induces acute inflammation with elevated pro-inflammatory markers in the pathogenesis of EVALI.

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“…16 The mammalian serine protease TMPRSS2 or the protease Furin (also known as Paired basic Amino acid Cleaving Enzyme) appear to prime the spike protein for interaction with ACE2. 17,18 SARS-CoV also binds to the cell-surface protein ACE2 and this binding is required for the virus to infect cells. 19 The binding of SARS-CoV-2 to ACE2 is enhanced compared to that of SARS-CoV due to several changes in the gene and hence amino acid sequence of the spike protein.…”

Section: Coronavirusesmentioning

confidence: 99%

The ocular surface, coronaviruses and COVID‐19

Willcox

Walsh

Nichols

et al. 2020

Clinical and Experimental Optometry

100

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A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Cited by 1,785 publications

References 45 publications

Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

Pulmonary toxicity and inflammatory response of e-cigarettes containing medium-chain triglyceride oil and vitamin E acetate: Implications in the pathogenesis of EVALI but independent of SARS-COV-2 COVID-19 related proteins

The ocular surface, coronaviruses and COVID‐19

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