The goal of this proposal is to define a novel signal transduction pathway that is activated by bacterial lipopolysaccharide (LPS), but does not require signaling by Toll-like Receptor 4 (TLR4). While TLR4 is widely recognized to control transcriptional responses to LPS, its role in controlling immediate (non-transcriptional) responses is less clear. Examples of such responses include endocytosis, phagocytosis, autophagy and tyrosine phosphorylation. How LPS triggers these activities is largely unknown, but we have discovered that non-transcriptional responses control the classically-defined transcriptional responses to LPS. Understanding how microbial products activate distinct signal transduction pathways may permit the design of drugs that can target a subset of pathways therapeutically. Our proposal is founded on our recent discovery that LPS-induces the endocytosis of TLR4 by a process that does not require TLR4 signaling. Rather TLR4 is cargo for an endocytosis pathway that is activated by the LPS-binding protein CD14. While TLR4 does not direct its own endocytosis, this process is essential for TLR4 to induce TRIF-dependent signal transduction from endosomes. Our discovery of a response to LPS that does not require TLR4 signaling is important, as this receptor is thought to mediate all responses to LPS (also known as endotoxin). In this grant application, we propose to 1) identify new cytosolic regulators of CD14-dependent endocytosis, 2) identify the extracellular interactions that are needed for CD14-dependent endocytosis, and 3) identify the importance of CD14-dependent endocytosis in encounters between macrophages and pathogenic Yersinia. Collectively, this work will provide important insight into the means by which non-transcriptional responses to LPS are controlled.

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 in-activation of immunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
Project #
Application #
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Palker, Thomas J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Boston
United States
Zip Code
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
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
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
Odendall, Charlotte; Dixit, Evelyn; Stavru, Fabrizia et al. (2014) Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nat Immunol 15:717-26
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
Bonham, Kevin S; Kagan, Jonathan C (2014) Endosomes as platforms for NOD-like receptor signaling. Cell Host Microbe 15:523-5

Showing the most recent 10 out of 14 publications