{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/129599"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/129599","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Identification of viral and cellular factors that modulate heterogeneity in IFN induction during influenza infection","abstract":"Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2027-05-01","abstract_html":"Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2027-05-01","abstract_has_math":false,"creators":["Rivera Cardona, Joel"],"institution":"University of Illinois Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Microbiology","degree_department":null,"school":null,"contributors":["Brooke, Christopher B","Wu, Nicholas C","Kieffer, Collin","Golding, Ido"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-04-30","date_published":"2025-04-30","updated_at":"2026-07-22T22:25:05Z","subjects":["influenza A virus","scRNA-seq","viral evolution","immune antagonism","RNA velocity","interferon","RNA sensing","antiviral response","innate immunity","interferon-stimulated genes","cellular heterogeneity"],"languages":["en","eng"],"rights":["Copyright 2025 Joel Rivera Cardona"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/129599","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Brooke, Christopher B","Wu, Nicholas C","Kieffer, Collin","Golding, Ido"]},{"key":"dc:creator","label":"Author","values":["Rivera Cardona, Joel"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-04-30","2025-05"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Microbiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["influenza A virus","scRNA-seq","viral evolution","immune antagonism","RNA velocity","interferon","RNA sensing","antiviral response","innate immunity","interferon-stimulated genes","cellular heterogeneity"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2025 Joel Rivera Cardona"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/129599"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2027-05-01","The student, Joel Rivera Cardona, accepted the attached license on 2025-04-28 at 19:55.","The student, Joel Rivera Cardona, submitted this Dissertation for approval on 2025-04-28 at 20:37.","This Dissertation was approved for publication on 2025-04-30 at 20:21.","DSpace SAF Submission Ingestion Package generated from Vireo submission #22054 on 2025-10-19 at 19:16:36","The ability of seasonal Influenza A viruses (IAVs) to persist in the human population relies on their ability to evade and subvert the host immune response. While the evolution of seasonal H1N1 and H3N2 viruses to escape humoral immunity is well characterized, relatively little is known about how these viruses have adapted to antagonize the innate immune response, especially the interferon signaling pathway. Despite the critical role of interferons (IFNs) in orchestrating antiviral defenses, single-cell studies have revealed that most infected cells fail to mount an IFN response. To better understand the factors driving this heterogeneity, we investigated both viral and cellular determinants of IFN induction in infected cells. To characterize the viral factors influencing IFN expression in the small subset of IFN-producing cells, we developed a flow cytometry-based method to examine transcriptional changes in IFN and interferon-stimulated gene (ISG) expression at single-cell resolution. Our findings show that NS segments derived from seasonal H3N2 viruses are more efficient at antagonizing IFN signaling but less effective at suppressing IFN induction compared to the pdm2009 H1N1 lineage. By analyzing a collection of NS segments spanning the evolutionary history of current seasonal IAV lineages, we observed long periods of stability in IFN antagonism potential with occasional phenotypic shifts. These findings highlight key differences in how seasonal and pandemic H1N1 and H3N2 viruses modulate the human IFN response at the single-cell level. Although viral immune antagonism plays a major role in shaping IFN induction, studies using synthetic immune agonists have shown that most cells still fail to produce IFNs, suggesting that host-intrinsic factors also contribute to this heterogeneity. To identify cellular determinants of IFN induction potential, we developed an approach to analyze temporal scRNA-seq data from IAV-infected cells. This analysis revealed that the intrinsic expression of specific ISGs in pre-infection cells correlates with IFN induction potential post-infection. Validation experiments confirmed that OASL expression is required for robust IFNL induction during IAV infection. These results uncover a novel role for IFN-independent, intrinsic ISG expression in promoting IFN induction and provide new insights into the mechanisms driving cell-to-cell heterogeneity in innate immune activation."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Identification of viral and cellular factors that modulate heterogeneity in IFN induction during influenza infection"]}]}],"canonical_facts":{"dc:contributor":["Brooke, Christopher B","Wu, Nicholas C","Kieffer, Collin","Golding, Ido"],"dc:creator":["Rivera Cardona, Joel"],"dc:date":["2025-04-30","2025-05"],"dc:description":["Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2027-05-01","The student, Joel Rivera Cardona, accepted the attached license on 2025-04-28 at 19:55.","The student, Joel Rivera Cardona, submitted this Dissertation for approval on 2025-04-28 at 20:37.","This Dissertation was approved for publication on 2025-04-30 at 20:21.","DSpace SAF Submission Ingestion Package generated from Vireo submission #22054 on 2025-10-19 at 19:16:36","The ability of seasonal Influenza A viruses (IAVs) to persist in the human population relies on their ability to evade and subvert the host immune response. While the evolution of seasonal H1N1 and H3N2 viruses to escape humoral immunity is well characterized, relatively little is known about how these viruses have adapted to antagonize the innate immune response, especially the interferon signaling pathway. Despite the critical role of interferons (IFNs) in orchestrating antiviral defenses, single-cell studies have revealed that most infected cells fail to mount an IFN response. To better understand the factors driving this heterogeneity, we investigated both viral and cellular determinants of IFN induction in infected cells. To characterize the viral factors influencing IFN expression in the small subset of IFN-producing cells, we developed a flow cytometry-based method to examine transcriptional changes in IFN and interferon-stimulated gene (ISG) expression at single-cell resolution. Our findings show that NS segments derived from seasonal H3N2 viruses are more efficient at antagonizing IFN signaling but less effective at suppressing IFN induction compared to the pdm2009 H1N1 lineage. By analyzing a collection of NS segments spanning the evolutionary history of current seasonal IAV lineages, we observed long periods of stability in IFN antagonism potential with occasional phenotypic shifts. These findings highlight key differences in how seasonal and pandemic H1N1 and H3N2 viruses modulate the human IFN response at the single-cell level. Although viral immune antagonism plays a major role in shaping IFN induction, studies using synthetic immune agonists have shown that most cells still fail to produce IFNs, suggesting that host-intrinsic factors also contribute to this heterogeneity. To identify cellular determinants of IFN induction potential, we developed an approach to analyze temporal scRNA-seq data from IAV-infected cells. This analysis revealed that the intrinsic expression of specific ISGs in pre-infection cells correlates with IFN induction potential post-infection. Validation experiments confirmed that OASL expression is required for robust IFNL induction during IAV infection. These results uncover a novel role for IFN-independent, intrinsic ISG expression in promoting IFN induction and provide new insights into the mechanisms driving cell-to-cell heterogeneity in innate immune activation."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/129599"],"dc:language":["en","eng"],"dc:rights":["Copyright 2025 Joel Rivera Cardona"],"dc:subject":["influenza A virus","scRNA-seq","viral evolution","immune antagonism","RNA velocity","interferon","RNA sensing","antiviral response","innate immunity","interferon-stimulated genes","cellular heterogeneity"],"dc:title":["Identification of viral and cellular factors that modulate heterogeneity in IFN induction during influenza infection"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Microbiology"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:05Z"}