Identification of viral and cellular factors that modulate heterogeneity in IFN induction during influenza infection
Rivera Cardona, Joel
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Permalink
https://hdl.handle.net/2142/129599
Description
Title
Identification of viral and cellular factors that modulate heterogeneity in IFN induction during influenza infection
Author(s)
Rivera Cardona, Joel
Issue Date
2025-04-30
Director of Research (if dissertation) or Advisor (if thesis)
Brooke, Christopher B
Doctoral Committee Chair(s)
Brooke, Christopher B
Committee Member(s)
Wu, Nicholas C
Kieffer, Collin
Golding, Ido
Department of Study
Microbiology
Discipline
Microbiology
Degree Granting Institution
University of Illinois Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
influenza A virus
scRNA-seq
viral evolution
immune antagonism
RNA velocity
interferon
RNA sensing
antiviral response
innate immunity
interferon-stimulated genes
cellular heterogeneity
Language
eng
Abstract
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.
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