Dataset Information

Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron.

ABSTRACT: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) binds to angiotensin-converting enzyme 2 (ACE2) to mediate membrane fusion via two distinct pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In this study, we found that SARS-CoV-2 S has a wider protease usage and can also be activated by TMPRSS13 and matrix metalloproteinases (MMPs). We found that MMP-2 and MMP-9 played roles in SARS-CoV-2 S cell-cell fusion and TMPRSS2- and cathepsin-independent viral entry in cells expressing high MMP levels. MMP-dependent viral entry required cleavage at the S1/S2 junction in viral producer cells, and differential processing of variants of concern S dictated its usage; the efficiently processed Delta S preferred metalloproteinase-dependent entry when available, and less processed Omicron S was unable to us metalloproteinases for entry. As MMP-2/9 are released during inflammation, they may play roles in S-mediated cytopathic effects, tropism, and disease outcome.

SUBMITTER: Benlarbi M

PROVIDER: S-EPMC9549715 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron.

Benlarbi Mehdi M Laroche Geneviève G Fink Corby C Fu Kathy K Mulloy Rory P RP Phan Alexandra A Ariana Ardeshir A Stewart Corina M CM Prévost Jérémie J Beaudoin-Bussières Guillaume G Daniel Redaet R Bo Yuxia Y El Ferri Omar O Yockell-Lelièvre Julien J Stanford William L WL Giguère Patrick M PM Mubareka Samira S Finzi Andrés A Dekaban Gregory A GA Dikeakos Jimmy D JD Côté Marceline M

iScience 20221010 11

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) binds to angiotensin-converting enzyme 2 (ACE2) to mediate membrane fusion via two distinct pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In this study, we found that SARS-CoV-2 S has a wider protease usage and can also be activated by TMPRSS13 and matrix metalloproteinases (MMPs). We found that MMP-2 and MMP-9 played roles in SARS-CoV-2 S cell-cell ...[more]

PMID: 36254158

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Project description:BACKGROUNDIncreased SARS-CoV-2 reinfection rates have been reported recently, with some locations basing reinfection on a second positive PCR test at least 90 days after initial infection. In this study, we used Johns Hopkins SARS-CoV-2 genomic surveillance data to evaluate the frequency of sequencing-validated, confirmed, and inferred reinfections between March 2020 and July 2022.METHODSPatients who had 2 or more positive SARS-CoV-2 tests in our system, with samples sequenced as a part of our surveillance efforts, were identified as the cohort for our study. SARS-CoV-2 genomes of patients' initial and later samples were compared.RESULTSA total of 755 patients (920 samples) had a positive test at least 90 days after the initial test, with a median time between tests of 377 days. Sequencing was attempted on 231 samples and was successful in 127. Rates of successful sequencing spiked during the Omicron surge; there was a higher median number of days from initial infection in these cases compared with those with failed sequences. A total of 122 (98%) patients showed evidence of reinfection; 45 of these patients had sequence-validated reinfection and 77 had inferred reinfections (later sequencing showed a clade that was not circulating when the patient was initially infected). Of the 45 patients with sequence-validated reinfections, 43 (96%) had reinfections that were caused by the Omicron variant, 41 (91%) were symptomatic, 32 (71%) were vaccinated prior to the second infection, 6 (13%) were immunosuppressed, and only 2 (4%) were hospitalized.CONCLUSIONSequence-validated reinfections increased with the Omicron surge but were generally associated with mild infections.FUNDINGFunding was provided by the Johns Hopkins Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C), CDC (75D30121C11061), Johns Hopkins University President's Fund Research Response, Johns Hopkins Department of Pathology, and the Maryland Department of Health.

Dataset Information

Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron.

Publications

Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron.

Similar Datasets

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