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 #
5R01AI093589-02
Application #
8223165
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
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
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
Brubaker, Sky W; Gauthier, Anna E; Mills, Eric W et al. (2014) A bicistronic MAVS transcript highlights a class of truncated variants in antiviral immunity. Cell 156:800-11
Odendall, Charlotte; Dixit, Evelyn; Stavru, Fabrizia et al. (2014) Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nat Immunol 15:717-26
Bonham, Kevin S; Kagan, Jonathan C (2014) Endosomes as platforms for NOD-like receptor signaling. Cell Host Microbe 15:523-5
Kagan, Jonathan C (2014) Common mechanisms activate plant guard receptors and TLR4. Trends Immunol 35:454-6
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
Bonham, Kevin S; Orzalli, Megan H; Hayashi, Kachiko et al. (2014) A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction. Cell 156:705-16
Kagan, Jonathan C (2013) Recognition for an innate explorer. Cell 154:261-4
Dixit, Evelyn; Kagan, Jonathan C (2013) Intracellular pathogen detection by RIG-I-like receptors. Adv Immunol 117:99-125
Cho, Jin A; Lee, Ann-Hwee; Platzer, Barbara et al. (2013) The unfolded protein response element IRE1* senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13:558-69