Dr. Greg Snyder, Institute of Human Virology, UMD.

Toll-like receptors constitute a family of pattern recognition receptors of the innate immune system that are activated in response to molecular patterns found on host, environmental or microbial stimuli. Receptor activation triggers a signal transduction cascade involving cytoplasmic domains that are shared among Toll-like and Interleukin-1 receptor (TIR) families that results in cytokine and chemokine-driven responses. Unregulated TIR‐based innate immune signaling has been implicated in numerous human diseases involving autoimmunity, inflammation, and associated diseases. Conversely, controlled activation of innate immune signal transduction is a promising pathway to novel and improved vaccine adjuvant design. Microbes have evolved mechanisms to regulate and evade innate immunity for infection, survival and pathogenesis. One such mechanism involves the direct subversion of innate immune signaling pathways by bacterial and viral Toll-IL-1R interacting proteins. Microbial TIR interacting proteins are thought to function predominantly by direct binding of their own TIR homology domains to host Toll-like and Interleukin-1 receptor and adaptor TIR domain containing proteins, which disrupts signaling events that would normally clear the pathogen. Microbial TIR proteins have been identified as virulence factors in several priority pathogens and have also been found in gut commensal bacteria. We propose that defining the molecular mechanisms by which microbial TIR proteins bind to host TIR domain proteins and subvert host TIR signaling will rationally inform and propel development of novel microbial derived therapeutics to counteract both microbial pathogenicity and TIR-mediated inflammatory diseases. Accordingly, we have structurally determined several key bacterial and host TIR proteins, defined their putative protein-protein interfaces and identified and characterized novel microbial derived inhibitory peptides and small molecule inhibitory compounds which protect against inflammation and death. Using a structure‐based, functionally verified drug design approach, our long-term goal is development of novel therapeutics that inhibit microbial pathogenesis and inflammation associated disease.