This proposal takes an innovative approach to address a critical question in innate immunity and cell biology: Where within infected cells are viruses detected? We have recently discovered that in addition to mitochondria, peroxisomes are signaling platforms for antiviral innate immune signaling. Peroxisome-mediated signaling occurs through the actions MAVS, an adaptor protein that receives signals from RIG-I, an RNA helicase that surveys the cytosol for viruses containing RNA genomes. MAVS signaling from peroxisomes induces an unusual interferon-independent signaling pathway that activates the rapid expression of antiviral factors. This signaling pathway is activated by diverse viruses such as influenza virus, vesicular stomatitis virus and mammalian reovirus, and is capable of restricting viral replication. Based on this discovery, we now seek to (1) determine how signaling from peroxisomes leads to the initiation of antiviral immunity, (2) determine if peroxisomal signaling is critical for the control of viruses that disrupt type I interferon expression, and how viral restriction is accomplished, and (3) characterize a novel negative regulator of RIG-I signaling that functions from peroxisomes and mitochondria. Our proposed studies have the potential to profoundly change our view of how antiviral immunity is organized within mammalian cells. This work may facilitate the design of novel therapeutics to manipulate the subcellular positioning of innate immune signaling molecules, helping to either trigger or interfere with an immune reaction.)

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093589-04
Application #
8610230
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Palker, Thomas J
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$435,000
Indirect Cost
$185,000
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Orzalli, Megan H; Kagan, Jonathan C (2017) Apoptosis and Necroptosis as Host Defense Strategies to Prevent Viral Infection. Trends Cell Biol 27:800-809
Franz, Kate M; Kagan, Jonathan C (2017) Innate Immune Receptors as Competitive Determinants of Cell Fate. Mol Cell 66:750-760
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
Tan, Yunhao; Kagan, Jonathan C (2017) Microbe-inducible trafficking pathways that control Toll-like receptor signaling. Traffic 18:6-17
Kagan, Jonathan C (2017) Lipopolysaccharide Detection across the Kingdoms of Life. Trends Immunol 38:696-704
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
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
Zanoni, Ivan; Tan, Yunhao; Di Gioia, Marco et al. (2016) An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352:1232-6
Brubaker, Sky W; Bonham, Kevin S; Zanoni, Ivan et al. (2015) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33:257-90
Odendall, Charlotte; Kagan, Jonathan C (2015) The unique regulation and functions of type III interferons in antiviral immunity. Curr Opin Virol 12:47-52

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