The Structural Basis of Pathogen Recognition by TLR Receptors of the Innate Immune System

The innate immune system is the first line of defense against invading pathogens. The overall goal of this project is to understand how a key family of innate immune receptors, the Toll-like receptors TLRs, recognize their microbial ligands, and how this recognition is translated into an immune response. This report covers an initial one-year contract in a three-year project. In our first year, we developed methods to purify milligram quantities of TLR5, TLR11 and TLR12, and of their ligands, bacterial flagellin and Toxoplasma profilin PFTG, respectively. We obtained crystals of TLR5, which diffract to 2.9-A resolution, and crystals of PFTG, which diffract to 1.9 A. We are currently pursuing the crystallographic structure determinations of TLR5 and PFTG. In parallel, we have obtained the first biochemical evidence for direct interaction between purified TLR5, TLR11 and flagellin. These results represent significant milestones towards our stated goal of understanding the molecular basis of pathogen recognition and signal generation by TLRs. Our work will guide efforts to design novel vaccine adjuvants.