Understanding the role of a novel Toll-like receptor

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Innate immune responses play a critical role in the protection of organisms against pathogens. Innate immune responses are primarily triggered upon recognition of pathogen-associated molecular patterns (PAMP) by a class of evolutionarily conserved receptors known as Toll-like receptors (TLRs). While other receptors, such as scavenger receptors on macrophages, also play important roles in innate immune responses, emerging knowledge strongly implicates Toll-receptors as the key molecules involved in this evolutionarily ancient immune response. Currently ten distinct Toll-receptors have been reported in the literature and studies have indicated that individual Toll-receptors serve to detect distinct molecular patterns, e.g. TLR5 binds flagellin, whereas TLR3 binds double stranded RNA. It also appears that the recognition properties of TLRs can be modified through homo-and hetero-dimerization of the TLRs. We have recently identified and cloned a novel Toll-like receptor that we have named TLR11. The pattern of expression of this receptor is non-overlapping with the other TLRs, and is primarily expressed in liver, kidney and bladder epithelial cells. Remarkably cells expressing TLR11 respond strongly to bacterial strains that have been implicated in urinary tract infections (UTI). This suggests that TLR11 may play a key role in mounting innate immune responses to pathogens in the urinary tract. TLR11 does not respond to any of the known PAMP's indicating that it responds to a novel PAMP that is expressed on certain uropathogenic bacteria. We are therefore proposing to further characterize the biological and molecular role of TLR11 using a combination of genetic, molecular and biochemical approaches. The specific objectives of our proposal will be to i) further characterize the cellular expression of TLR11 in kidney and bladder epithelial cells, and determine whetherTLR11 functions with other TLRs, e.g. TLR5, to mediate its signaling function, ii) identify the TLR11-specific ligand using biochemical and genetic approaches, iii) create a knock-out mouse strain and use it to study the role of TLR11 in urinary tract infections. Characterization of TLR11 and identification of its specific ligand will provide the opportunity to create a novel vaccination strategy against UTI in the future.