{"id":{"repo_id":"utmb","oai_identifier":"oai:utmb-ir.tdl.org:2152.3/12050"},"canonical_url":"https://search.dev.ndltd.org/etd/utmb/oai:utmb-ir.tdl.org:2152.3/12050","repository":{"repo_id":"utmb","name":"University of Texas Medical Branch","base_url":"https://utmb-ir.tdl.org/server/oai/request"},"display":{"title":"Deletions in SARS-CoV-2 nsp6 enhance antagonism of type-I interferon signaling","abstract":"Severe 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.","abstract_html":"Severe 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.","abstract_has_math":false,"creators":["Bills, Cody Jay 1993-"],"institution":"The University of Texas Medical Branch at Galveston","degree_name":"Biochemistry and Molecular Biology (Doctoral)","degree_level":null,"degree_discipline":"Biomedical Sciences","degree_department":null,"school":null,"contributors":[],"advisors":["Routh, Andrew (alrouth@utmb.edu)","Shi, Pei-Yong (peshi@utmb.edu)"],"committee_chairs":[],"committee_members":["Leiman, Petr (pgleiman@utmb.edu)","Ward, Michelle (miward@utmb.edu)","Wilusz, Jeffrey (jeffrey.wilusz@colostate.edu)"],"year":2023,"date_issued":"2023-05-01T06:00:00.000Z","date_published":"2023-05-01T06:00:00.000Z","updated_at":"2026-07-24T05:50:54Z","subjects":[],"languages":["English"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2152.3/12050","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Routh, Andrew (alrouth@utmb.edu)","Shi, Pei-Yong (peshi@utmb.edu)"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Leiman, Petr (pgleiman@utmb.edu)","Ward, Michelle (miward@utmb.edu)","Wilusz, Jeffrey (jeffrey.wilusz@colostate.edu)"]},{"key":"dc:creator","label":"Author","values":["Bills, Cody Jay 1993-"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2023-05-24T14:25:53Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2023-05-24T14:25:53Z"]},{"key":"dc:date.issued","label":"Date","values":["2023-05-01T06:00:00.000Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biomedical Sciences"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Biochemistry and Molecular Biology (Doctoral)"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The University of Texas Medical Branch at Galveston"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["English"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/2152.3/12050"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Severe 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."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Deletions in SARS-CoV-2 nsp6 enhance antagonism of type-I interferon signaling"]}]}],"canonical_facts":{"dc:contributor.advisor":["Routh, Andrew (alrouth@utmb.edu)","Shi, Pei-Yong (peshi@utmb.edu)"],"dc:contributor.committeemember":["Leiman, Petr (pgleiman@utmb.edu)","Ward, Michelle (miward@utmb.edu)","Wilusz, Jeffrey (jeffrey.wilusz@colostate.edu)"],"dc:creator":["Bills, Cody Jay 1993-"],"dc:date.accessioned":["2023-05-24T14:25:53Z"],"dc:date.available":["2023-05-24T14:25:53Z"],"dc:date.issued":["2023-05-01T06:00:00.000Z"],"dc:description.abstract":["Severe 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.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/2152.3/12050"],"dc:language.iso":["English"],"dc:title":["Deletions in SARS-CoV-2 nsp6 enhance antagonism of type-I interferon signaling"],"dc:type":["Thesis"],"thesis:degree_discipline":["Biomedical Sciences"],"thesis:degree_name":["Biochemistry and Molecular Biology (Doctoral)"],"thesis:institution_name":["The University of Texas Medical Branch at Galveston"]},"updated_at":"2026-07-24T05:50:54Z"}