{"id":{"repo_id":"utmb","oai_identifier":"oai:utmb-ir.tdl.org:2152.3/647"},"canonical_url":"https://search.dev.ndltd.org/etd/utmb/oai:utmb-ir.tdl.org:2152.3/647","repository":{"repo_id":"utmb","name":"University of Texas Medical Branch","base_url":"https://utmb-ir.tdl.org/server/oai/request"},"display":{"title":"MyD88-Mediated Signaling in Protective Immunity against an Attenuated West Nile Virus Infection","abstract":"West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant is highly attenuated in mice. Interestingly, it induces strong immune responses and protects mice from subsequent lethal wild-type WNV NY99 infection. These features have important applications in flavivirus vaccine development. The goal of my dissertation is to understand the underlying mechanisms of WNV NS4B-P38G induced protective immunity. Toll-like receptor (TLR) 7/myeloid differentiation factor 88 (MyD88)-mediated signaling pathways protect host against wild-type WNV infection. Both MyD88-/- and TLR7-/- mice had reduced effector T cell functions compared to wild-type mice following NS4B-P38G mutant infection. TLR7-/- mice displayed normal memory T cell functions and were fully protected from secondary challenge lethal WNV NY99. MyD88-/- mice had reduced memory T cell responses and were partially protected. These results suggest that TLR7-dependent-MyD88 signaling is required for T cell priming during NS4B-P38G vii mutant infection. Whereas the TLR7-independent-MyD88 signaling pathways are involved in memory T cell development, which may contribute to host protection during secondary challenge with NY99. Aging is a risk factor for WNV encephalitis. Similar to TLR7-/- mice, old mice had reduced effector T cells and were partially protected from primary WNV NS4B-P38G mutant infection, but had normal memory T cell response and were all protected from re-challenge with WNV NY99. An impaired TLR7 signaling in old DCs led to lower innate cytokine response and a reduced antigen-presenting capacity compared to young DCs. I also used two human cell lines-THP-1 and THP-1 macrophages to study the immune response following NS4B-P38G infection. NS4B-P38G mutant produced more viral RNA than parental NY99 in both cell types and boosted higher innate cytokine responses with no detectable infective virus. NS4B-P38G mutant infection in THP-1 cells led to more diverse and robust innate cytokine responses than that seen in THP-1 macrophages, which were mediated by TLR7 and retinoic acid-inducible gene 1 (RIG-I) signaling pathways. Thus, a defective viral life cycle during NS4B-P38G mutant infection in human monocytic and macrophage cells leads to more potent cell intrinsic innate cytokine responses. In summary, my dissertation studies suggest that MyD88-mediated signaling pathway regulates protective immune response to WNV NS4B-P38G mutant infection.","abstract_html":"West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant is highly attenuated in mice. Interestingly, it induces strong immune responses and protects mice from subsequent lethal wild-type WNV NY99 infection. These features have important applications in flavivirus vaccine development. The goal of my dissertation is to understand the underlying mechanisms of WNV NS4B-P38G induced protective immunity. Toll-like receptor (TLR) 7/myeloid differentiation factor 88 (MyD88)-mediated signaling pathways protect host against wild-type WNV infection. Both MyD88-/- and TLR7-/- mice had reduced effector T cell functions compared to wild-type mice following NS4B-P38G mutant infection. TLR7-/- mice displayed normal memory T cell functions and were fully protected from secondary challenge lethal WNV NY99. MyD88-/- mice had reduced memory T cell responses and were partially protected. These results suggest that TLR7-dependent-MyD88 signaling is required for T cell priming during NS4B-P38G vii mutant infection. Whereas the TLR7-independent-MyD88 signaling pathways are involved in memory T cell development, which may contribute to host protection during secondary challenge with NY99. Aging is a risk factor for WNV encephalitis. Similar to TLR7-/- mice, old mice had reduced effector T cells and were partially protected from primary WNV NS4B-P38G mutant infection, but had normal memory T cell response and were all protected from re-challenge with WNV NY99. An impaired TLR7 signaling in old DCs led to lower innate cytokine response and a reduced antigen-presenting capacity compared to young DCs. I also used two human cell lines-THP-1 and THP-1 macrophages to study the immune response following NS4B-P38G infection. NS4B-P38G mutant produced more viral RNA than parental NY99 in both cell types and boosted higher innate cytokine responses with no detectable infective virus. NS4B-P38G mutant infection in THP-1 cells led to more diverse and robust innate cytokine responses than that seen in THP-1 macrophages, which were mediated by TLR7 and retinoic acid-inducible gene 1 (RIG-I) signaling pathways. Thus, a defective viral life cycle during NS4B-P38G mutant infection in human monocytic and macrophage cells leads to more potent cell intrinsic innate cytokine responses. In summary, my dissertation studies suggest that MyD88-mediated signaling pathway regulates protective immune response to WNV NS4B-P38G mutant infection.","abstract_has_math":false,"creators":["Xie, Guorui"],"institution":"The University of Texas Medical Branch at Galveston","degree_name":"Microbiology and Immunology (Doctoral)","degree_level":"Doctoral","degree_discipline":"Immunology and Infection Disease","degree_department":null,"school":null,"contributors":[],"advisors":["Wang, Tian"],"committee_chairs":[],"committee_members":["Aguilar, Patricia","Barrett, Alan","Blitvich, Bradley","Cong, Yingzi"],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T05:51:09Z","subjects":["MyD88, TLR7, NS4B-P38G mutant, West Nile virus, THP-1, old mice, young mice, T cells, Dentritic Cells, cytokine,"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2152.3/647","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Wang, Tian"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Aguilar, Patricia","Barrett, Alan","Blitvich, Bradley","Cong, Yingzi"]},{"key":"dc:creator","label":"Author","values":["Xie, Guorui"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2016-05-05T21:22:14Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2016-05-05T21:22:14Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Immunology and Infection Disease"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Microbiology and Immunology (Doctoral)"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The University of Texas Medical Branch at Galveston"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["MyD88, TLR7, NS4B-P38G mutant, West Nile virus, THP-1, old mice, young mice, T cells, Dentritic Cells, cytokine,"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/2152.3/647"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant is highly attenuated in mice. Interestingly, it induces strong immune responses and protects mice from subsequent lethal wild-type WNV NY99 infection. These features have important applications in flavivirus vaccine development. The goal of my dissertation is to understand the underlying mechanisms of WNV NS4B-P38G induced protective immunity. Toll-like receptor (TLR) 7/myeloid differentiation factor 88 (MyD88)-mediated signaling pathways protect host against wild-type WNV infection. Both MyD88-/- and TLR7-/- mice had reduced effector T cell functions compared to wild-type mice following NS4B-P38G mutant infection. TLR7-/- mice displayed normal memory T cell functions and were fully protected from secondary challenge lethal WNV NY99. MyD88-/- mice had reduced memory T cell responses and were partially protected. These results suggest that TLR7-dependent-MyD88 signaling is required for T cell priming during NS4B-P38G vii mutant infection. Whereas the TLR7-independent-MyD88 signaling pathways are involved in memory T cell development, which may contribute to host protection during secondary challenge with NY99. Aging is a risk factor for WNV encephalitis. Similar to TLR7-/- mice, old mice had reduced effector T cells and were partially protected from primary WNV NS4B-P38G mutant infection, but had normal memory T cell response and were all protected from re-challenge with WNV NY99. An impaired TLR7 signaling in old DCs led to lower innate cytokine response and a reduced antigen-presenting capacity compared to young DCs. I also used two human cell lines-THP-1 and THP-1 macrophages to study the immune response following NS4B-P38G infection. NS4B-P38G mutant produced more viral RNA than parental NY99 in both cell types and boosted higher innate cytokine responses with no detectable infective virus. NS4B-P38G mutant infection in THP-1 cells led to more diverse and robust innate cytokine responses than that seen in THP-1 macrophages, which were mediated by TLR7 and retinoic acid-inducible gene 1 (RIG-I) signaling pathways. Thus, a defective viral life cycle during NS4B-P38G mutant infection in human monocytic and macrophage cells leads to more potent cell intrinsic innate cytokine responses. In summary, my dissertation studies suggest that MyD88-mediated signaling pathway regulates protective immune response to WNV NS4B-P38G mutant infection."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["MyD88-Mediated Signaling in Protective Immunity against an Attenuated West Nile Virus Infection"]}]}],"canonical_facts":{"dc:contributor.advisor":["Wang, Tian"],"dc:contributor.committeemember":["Aguilar, Patricia","Barrett, Alan","Blitvich, Bradley","Cong, Yingzi"],"dc:creator":["Xie, Guorui"],"dc:date.accessioned":["2016-05-05T21:22:14Z"],"dc:date.available":["2016-05-05T21:22:14Z"],"dc:description.abstract":["West Nile virus (WNV) nonstructural (NS) 4B-P38G mutant is highly attenuated in mice. Interestingly, it induces strong immune responses and protects mice from subsequent lethal wild-type WNV NY99 infection. These features have important applications in flavivirus vaccine development. The goal of my dissertation is to understand the underlying mechanisms of WNV NS4B-P38G induced protective immunity. Toll-like receptor (TLR) 7/myeloid differentiation factor 88 (MyD88)-mediated signaling pathways protect host against wild-type WNV infection. Both MyD88-/- and TLR7-/- mice had reduced effector T cell functions compared to wild-type mice following NS4B-P38G mutant infection. TLR7-/- mice displayed normal memory T cell functions and were fully protected from secondary challenge lethal WNV NY99. MyD88-/- mice had reduced memory T cell responses and were partially protected. These results suggest that TLR7-dependent-MyD88 signaling is required for T cell priming during NS4B-P38G vii mutant infection. Whereas the TLR7-independent-MyD88 signaling pathways are involved in memory T cell development, which may contribute to host protection during secondary challenge with NY99. Aging is a risk factor for WNV encephalitis. Similar to TLR7-/- mice, old mice had reduced effector T cells and were partially protected from primary WNV NS4B-P38G mutant infection, but had normal memory T cell response and were all protected from re-challenge with WNV NY99. An impaired TLR7 signaling in old DCs led to lower innate cytokine response and a reduced antigen-presenting capacity compared to young DCs. I also used two human cell lines-THP-1 and THP-1 macrophages to study the immune response following NS4B-P38G infection. NS4B-P38G mutant produced more viral RNA than parental NY99 in both cell types and boosted higher innate cytokine responses with no detectable infective virus. NS4B-P38G mutant infection in THP-1 cells led to more diverse and robust innate cytokine responses than that seen in THP-1 macrophages, which were mediated by TLR7 and retinoic acid-inducible gene 1 (RIG-I) signaling pathways. Thus, a defective viral life cycle during NS4B-P38G mutant infection in human monocytic and macrophage cells leads to more potent cell intrinsic innate cytokine responses. In summary, my dissertation studies suggest that MyD88-mediated signaling pathway regulates protective immune response to WNV NS4B-P38G mutant infection."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["http://hdl.handle.net/2152.3/647"],"dc:subject":["MyD88, TLR7, NS4B-P38G mutant, West Nile virus, THP-1, old mice, young mice, T cells, Dentritic Cells, cytokine,"],"dc:title":["MyD88-Mediated Signaling in Protective Immunity against an Attenuated West Nile Virus Infection"],"dc:type":["Thesis"],"thesis:degree_discipline":["Immunology and Infection Disease"],"thesis:degree_level":["Doctoral"],"thesis:degree_name":["Microbiology and Immunology (Doctoral)"],"thesis:institution_name":["The University of Texas Medical Branch at Galveston"]},"updated_at":"2026-07-24T05:51:09Z"}