The goal of this proposal is to characterize a protein complex called the myddosome, which is uniquely assembled during Toll-like Receptor (TLR) signal transduction. The myddosome is one of several newly- defined receptor-proximal complexes that control innate immune signal transduction. Analogous complexes operate to control inflammasome assembly and the RIG-I and TNF receptor signaling pathways. A common feature of these complexes is that they operate as organelles that are assembled ?on-demand?, or upon ligand binding. As such, these complexes are only present in cells after microbes have been detected, and they may serve as critical hubs for coordinating downstream signaling enzyme activation. Despite the recognition that these organelles control innate immunity, we have little understanding of their regulation (or composition). Our proposal is founded on our recent discovery that the myddosome is assembled within macrophages upon treatment with TLR ligands. This finding is important because it had been unclear whether the myddosome is a pre-existing protein complex, or if it is assembled inducibly. The inducible assembly of this complex provided us with a tool to study its regulation, and we recently identified the TLR sorting adaptor TIRAP as the first regulator of myddosome assembly. These discoveries establish the myddosome as an important model to study receptor-proximal protein complexes that define the signaling pathways of the innate immune system. In this application, we propose to explore how known myddosome components interact to regulate TLR signaling in vitro and in vivo (Aim 1), to explore how a new myddosome component regulates TLR signaling (Aim 2), and to explore the mechanisms underlying several mutant myddosome components that cause mouse or human disease (Aim 3).

Public Health Relevance

The collateral tissue damage that results from an immune response can cause life-threatening maladies that are sometimes more dangerous than the infection itself. Our research proposal sets out to understand the means by which an immune response is set into motion. By focusing our work on the earliest triggers of immune activation (the detection of microbes) we may unravel new means by which we can control the activation or inactivation of immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116550-03
Application #
9598324
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Jiang, Chao
Project Start
2016-12-13
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Evavold, Charles L; Ruan, Jianbin; Tan, Yunhao et al. (2018) The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity 48:35-44.e6
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
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
Kagan, Jonathan C (2017) Lipopolysaccharide Detection across the Kingdoms of Life. Trends Immunol 38:696-704