The goal of this proposal is to identify how interleukin-1 (IL-1) family cytokines induce the expression of interferons (IFNs) and IFN-stimulated genes (ISGs) to elicit an antiviral state in human cells. While the ability of pattern recognition receptrs (PRRs) to induce IFNs is well-recognized, cytokine receptors are not considered robust activators of IFN expression. Despite this view, several reports from the 1980s highlighted antiviral actions of IL-1, although the mechanisms underlying these activities have remained unclear. This proposal is founded on our discovery that IL-1 family members elicit the expression of Type I and Type III IFNs in primary human cells. While Type I IFNs are important regulators of immunity in all tissues, Type III IFNs are most critical at mucosal surfaces, where they are highly induced by viral infections (especially in humans). We recently identified the RIG-I/MAVS pathway as the principle means by which RNA viruses elicit Type III IFN expression in epithelial cells and hepatocytes, but the mechanisms by which IL-1 family members elicit similar antiviral responses is unclear. Explaining the importance and mechanisms of cytokine- and PRR-mediated antiviral responses will illuminate the complex regulatory events that promote host defense during infections. We hypothesize that an uncharacterized signal transduction pathway is activated by IL-1 family members to specifically promote an antiviral response. Moreover, we speculate that this antiviral pathway is most important during infections with viruses that prevent IFN expression or signaling. Under these conditions, inflammasome activation (or necrosis) results in the release of IL-1 family members that activate antiviral responses in uninfected neighboring cells. In contrast, during infections with less pathogenic viruses, the classic PRR-mediated IFN responses may be most critical to activate antiviral responses. This hypothesis prompts us to classify IL-1 family members as latent IFNs, whose main benefit may be to ensure that antiviral responses are induced in infected tissues, even during encounters with viruses that block IFN expression. In this proposal, we will explore key aspects of this hypothesis. Specifically, we will determine the genetic and biochemical basis for the antiviral IL-1 signaling pathway (Aim 1), determine the mechanism by which a key regulator of IL-1 induced antiviral responses, the transcription factor IRF1, is activated (Aim 2), and determine if the main function of IL-1 induced antiviral activity i to prevent the replication highly virulent viral pathogens (Aim 3). These studies will provide important insight into the relationship between cytokine receptors and PRRs, and their relative roles in controlling viral infections.
Compared to bacterial infections, there is an alarming lack of effective therapeutics to treat viral infections. Our research proposal seeks to understand how our antiviral immune responses are set into motion, with the ultimate goal of harnessing our immune defenses to specifically eliminate infections. By focusing on the earliest triggers of immune activation (the detection of viruses that enter our cells) we hope to uncover antiviral defense strategies that might be applicable to fight all infections.
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|Franz, Kate M; Neidermyer, William J; Tan, Yee-Joo et al. (2018) STING-dependent translation inhibition restricts RNA virus replication. Proc Natl Acad Sci U S A 115:E2058-E2067|
|Evavold, Charles L; Kagan, Jonathan C (2018) How Inflammasomes Inform Adaptive Immunity. J Mol Biol 430:217-237|
|Odendall, Charlotte; Voak, Andrew A; Kagan, Jonathan C (2017) Type III IFNs Are Commonly Induced by Bacteria-Sensing TLRs and Reinforce Epithelial Barriers during Infection. J Immunol 199:3270-3279|
|Franz, Kate M; Kagan, Jonathan C (2017) Innate Immune Receptors as Competitive Determinants of Cell Fate. Mol Cell 66:750-760|
|Rosadini, Charles V; Kagan, Jonathan C (2017) Early innate immune responses to bacterial LPS. Curr Opin Immunol 44:14-19|
|Tan, Yunhao; Kagan, Jonathan C (2017) Microbe-inducible trafficking pathways that control Toll-like receptor signaling. Traffic 18:6-17|
|Chow, Jonathan; Márka, Zsuzsa; Bartos, Imre et al. (2017) Environmental Stress Causes Lethal Neuro-Trauma during Asymptomatic Viral Infections. Cell Host Microbe 22:48-60.e5|
|Zanoni, Ivan; Tan, Yunhao; Di Gioia, Marco et al. (2017) By Capturing Inflammatory Lipids Released from Dying Cells, the Receptor CD14 Induces Inflammasome-Dependent Phagocyte Hyperactivation. Immunity 47:697-709.e3|
|Orzalli, Megan H; Kagan, Jonathan C (2017) Apoptosis and Necroptosis as Host Defense Strategies to Prevent Viral Infection. Trends Cell Biol 27:800-809|
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