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
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
Rosadini, Charles V; Kagan, Jonathan C (2016) Early innate immune responses to bacterial LPS. Curr Opin Immunol 44:14-19
Rosadini, Charles V; Zanoni, Ivan; Odendall, Charlotte et al. (2015) A Single Bacterial Immune Evasion Strategy Dismantles Both MyD88 and TRIF Signaling Pathways Downstream of TLR4. Cell Host Microbe 18:682-93
Chow, Jonathan; Franz, Kate M; Kagan, Jonathan C (2015) PRRs are watching you: Localization of innate sensing and signaling regulators. Virology 479-480:104-9
Rosadini, Charles V; Kagan, Jonathan C (2015) Microbial strategies for antagonizing Toll-like-receptor signal transduction. Curr Opin Immunol 32:61-70
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
Tan, Yunhao; Zanoni, Ivan; Cullen, Thomas W et al. (2015) Mechanisms of Toll-like Receptor 4 Endocytosis Reveal a Common Immune-Evasion Strategy Used by Pathogenic and Commensal Bacteria. Immunity 43:909-22
Franz, Kate M; Kagan, Jonathan C (2014) Finding a needle in a haystack of needles - a productive hunt for interferon stimulated genes with antiviral activity. Immunol Cell Biol 92:205-7
Tan, Yunhao; Kagan, Jonathan C (2014) A cross-disciplinary perspective on the innate immune responses to bacterial lipopolysaccharide. Mol Cell 54:212-23

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