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"Roles of IFN-λ in Intestinal Immunity to Virus Infection"

by
Jian-Da Lin
Molecular Pathology and Immunology Program
M.S. 2007, National Cheng Kung University, Taiwan
B.S. 2005, National Chiayi University, Taiwan


Thesis Advisor: Sergei V. Kotenko, Ph.D.
Professor
Department of Microbiology, Biochemistry & Molecular Genetics

Tuesday, April 19, 2016
9:00 A.M., Cancer Center Conference Room G-1196


Abstract

Type I (IFN-α/β) and type III (IFN-λ) interferons (IFNs) exert shared antiviral activities through distinct receptors. However, their relative importance for antiviral protection of different organ systems against specific viruses remains to be fully explored. We used mouse strains deficient in type-specific IFN signaling, STAT1 and Rag2 to dissect distinct and overlapping contributions of type I and type III IFNs to protection against homologous murine (EW-RV strain) and heterologous (non-murine) simian (RRV strain) rotavirus infections in suckling mice. Experiments demonstrated that murine EW-RV is insensitive to the action of both types of IFNs, and that timely viral clearance depends upon adaptive immune responses. In contrast, both type I and type III IFNs can control replication of the heterologous simian RRV in the gastrointestinal (GI) tract, and they cooperate to limit extra-intestinal simian RRV replication. Surprisingly, intestinal epithelial cells (IECs) were sensitive to both IFN types in neonatal mice, although their responsiveness to type I, but not type III IFNs, diminished in adult mice, revealing an unexpected age-dependent change in specific contribution of type I versus type III IFNs to antiviral defenses in the GI tract. Transcriptional analysis revealed that intestinal antiviral responses to RV are triggered through either type of IFN receptor, and are greatly diminished when receptors for both IFN types are lacking. These results also demonstrate a murine host-specific resistance to IFN-mediated antiviral effects by murine EW-RV, but the retention of host efficacy through the cooperative action by type I and type III IFNs in restricting heterologous simian RRV growth and systemic replication in suckling mice. Unexpectedly, we also observed that although type III IFNs limited RV replication in the small bowel, they promoted diarrheal disease by sensitizing IECs to RV-induced apoptosis. This is the first evidence of the ability of type III IFNs to play not only protective but also pathological roles during viral infection, suggesting that their expression and action should be well-balanced and controlled. Collectively, our findings reveal a well-orchestrated spatial and temporal tuning of innate antiviral responses in the intestinal tract where two types of IFNs through distinct patterns of their expression and distinct but overlapping sets of target cells coordinately regulate antiviral defenses against heterologous or homologous rotaviruses with substantially different effectiveness.


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