Deletions in SARS-CoV-2 nsp6 enhance antagonism of type-I interferon signaling

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dc.contributor.advisorRouth, Andrew (alrouth@utmb.edu)
dc.contributor.advisorShi, Pei-Yong (peshi@utmb.edu)
dc.contributor.committeeMemberLeiman, Petr (pgleiman@utmb.edu)
dc.contributor.committeeMemberWard, Michelle (miward@utmb.edu)
dc.contributor.committeeMemberWilusz, Jeffrey (jeffrey.wilusz@colostate.edu)
dc.creatorBills, Cody Jay 1993-
dc.creator.orcid0000-0001-9518-2203
dc.date.accessioned2023-05-24T14:25:53Z
dc.date.available2023-05-24T14:25:53Z
dc.date.created2023-05
dc.date.issued2023-05-01T06:00:00.000Z
dc.date.submittedMay 2023
dc.date.updated2023-05-24T14:25:54Z
dc.description.abstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and adapt long after it first emerged in 2019. As the causative agent of the coronavirus disease 2019 (COVID-19), a tremendous effort has been made to understand the molecular pathogenesis of SARS-CoV-2. Recent research has identified nonstructural protein 6 (nsp6) as a major contributor to SARS-CoV-2 replication through the formation of replication organelles, antagonism of interferon type I (IFN-I) responses, and NLRP3 inflammasome activation, a major factor of severe COVID-19. Here, I review the most recent published findings regarding the multiple roles of nsp6 in promoting SARS-CoV-2 replication and investigate further the effect of variant nsp6 mutations in molecular pathogenesis of SARS-CoV-2, specifically the antagonism of IFN-I pathways. I demonstrate that a mutant SARS-CoV-2 USA/WA1-2020 (WA1) containing a nsp6 mutation (ΔSGF-WA1) seen in the Alpha (B.1.1.7) and Omicron sublineages (BA.2, BA.4, BA.5) is less susceptible to IFN-α treatment in African green monkey kidney epithelial cells expressing the human co-factor TMPRSS2 (Vero E6-TMPRSS2) compared to full-length WA1. Nsp6 mutations ΔSGF and ΔLSG, a similar deletion found in BA.1 nsp6, augment the ability of nsp6 to block phosphorylation of STAT1 and STAT2 in vitro compared to WA1 nsp6, thereby suppressing the IFN-I signaling pathway. Furthermore, ΔSGF-WA1 infection of primary airway cultures secretes similar levels of infectious virus and viral RNA than WA1-infected cells but produces higher levels of intracellular viral RNA than WA1 and outcompetes parental WA1 in a competition experiment. Lastly, ΔSGF-WA1 infected mice have higher levels of viral RNA than WA1-infected mice and experience lower survival rates with a longer disease period. These data suggest that variants containing ΔSGF or ΔLSG mutations are more virulent and may cause more severe disease in COVID-19 patients.
dc.format.mimetypeapplication/pdf
dc.identifier.uri
dc.identifier.urihttps://hdl.handle.net/2152.3/12050
dc.language.isoEnglish
dc.subject.otherSARS-CoV-2
dc.subject.othernsp6
dc.subject.othermutation
dc.subject.otherpathogenesis
dc.subject.othervirus
dc.subject.otherinterferon
dc.subject.otherIFN
dc.subject.othercytokine storm
dc.subject.otherCOVID-19
dc.titleDeletions in SARS-CoV-2 nsp6 enhance antagonism of type-I interferon signaling
dc.typeThesis
dc.type.materialtext
thesis.degree.collegeUTMB Graduate School of Biomedical Sciences
thesis.degree.departmentBiochemistry, Cell, and Molecular Biology
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorThe University of Texas Medical Branch at Galveston
thesis.degree.nameBiochemistry and Molecular Biology (Doctoral)
thesis.degree.schoolUniversity of Texas Medical Branch

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