Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity
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Abstract
Abstract The SARS-CoV-2 Omicron BA.1 variant emerged in 2021 1 and has multiple mutations in its spike protein 2 . Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2 , and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways 3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.
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The record
- Venue
- Nature
- Topic
- SARS-CoV-2 and COVID-19 Research
- Field
- Medicine
- Canadian institutions
- —
- Funders
- Strategic International Collaborative Research ProgramCore Research for Evolutional Science and TechnologyInstitute of GeneticsNational Institute of Allergy and Infectious DiseasesResearch Institute for Microbial Diseases, Osaka UniversityJapan Society for the Promotion of ScienceSouth African Medical Research CouncilNational Institutes of HealthRosetrees TrustNIHR BioResourceUniversity of CambridgeAcademy of Medical SciencesMedical Research CouncilDepartment of Health and Social CareNHS Blood and TransplantNational Institute for Health and Care ResearchFast GrantsEngineering and Physical Sciences Research CouncilUK Research and InnovationTokyo Biochemical Research FoundationWellcome TrustEuropean Association for the Study of the LiverNational Institute of General Medical SciencesBurroughs Wellcome FundHoward Hughes Medical InstituteMitsubishi FoundationTakeda Science FoundationNewcastle UniversityJapan Agency for Medical Research and DevelopmentBill and Melinda Gates Foundation
- Keywords
- VirologyInfectivityVirusViral entryBiologyChemistryViral replicationMolecular biology
- Has abstract in OpenAlex
- yes