- Prof. Yorgo Modis, Principal Investigator
- Dr Ryuta Kanai, Postdoctoral Fellow
- Ms Christina Newman, Technician
- Ms Kaury Eisenman, Graduate Student
- Prof. Ruslan Medzhitov, Consultant
- Yale University, New Haven, USA
- The Structural Basis of Innate Immune Sensing and Signaling by Toll-Like Receptors
We rely on our innate immune system as the first line of defense against invading pathogens. The most important molecular sentinels of the innate immune system are the toll-like receptors (TLRs). Upon exposure to a microbe, TLRs recognize pathogen-associated molecular structures. This recognition event triggers an inflammatory response, which normally serves to fight infection by recruiting and activating various components of the adaptive immune system. However, TLR signaling causes inflammation following exposure to microbes during or after organ transplantation, especially in transplanted lungs, which are continually exposed to the environment. There is also mounting evidence that TLRs can cause inflammation even in the absence of microbes, in response to endogenous ligands released upon tissue injury, including injuries associated with solid organ transplantation. The combination of microbe-driven and endogenous TLR signaling in organ transplant recipients results in local inflammation in damaged or exposed regions of the grafted organ. Inflammatory compounds at these sites ultimately lead to the recruitment of armed T cells to the graft. It is these T cells that are principally responsible for graft destruction and acute graft rejection.
We propose to determine a three-dimensional structure of a TLR bound to the ligand that it recognizes. Knowing the three-dimensional structure of a molecule provides a deep understanding of how the molecule functions, and structures often suggest methods to control molecular function. Observing the structural changes that TLR undergoes as it recognizes microbial components will help us understand how this recognition event is translated into an inflammatory signal. We propose a rational, structure-based strategy to guide the design of novel TLR inhibitors. By reducing pathogen-induced inflammation, these inhibitors will provide new means to prevent inflammation and induce graft tolerance in solid organ transplant recipients.