Role of Toll-Like Receptors in Bacterial Keratitis

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DESCRIPTION (provided by applicant): Pseudomonas aeruginosa (P. aeruginosa) is a common organism associated with bacterial keratitis, especially in extended wear contact lens users. In the United States, the incidence of microbial keratitis is 25,000-30,000 cases annually with cost of treatment estimated at $15-30 million, making the disease of considerable medical and economic impact. In the studies proposed, we will test the overall hypothesis that Toll-like receptor/interleukin-1 receptor (TLR/IL-IR) and their associated molecules (e.g., CD14) play a critical role in the initial (innate) immune response in the cornea and are responsible for the disparate outcome to P. aeruginosa infection of B6 and BALB/c mice. No other laboratory is studying the role of this family of receptors in the eye using a bacterial (non-sterile) keratitis model. Three aims are proposed that will test the hypotheses that: 1) expression levels/distribution of TLR/IL-1Rs (TLR-4, -9, ST2 and SIGIRR) and related molecules (CD14, MD2) in epithelium and stroma are disparate in B6 and BALB/c mice in normal and/or P. aeruginosa infected cornea; 2) the TLR/IL1-R MyD88 vs. TRIF signaling pathway is preferentially activated in susceptible vs. resistant mice after bacterial infection; and 3) adaptive immunity (Th1 vs. Th2 responsiveness) is regulated disparately by TLR/IL-1Rs and their signaling molecules in the infected cornea of B6 vs. BALB/c mice. Thus, the goal of the studies proposed in this application is to elucidate the role of TLR/IL-1R in the innate and adaptive immune response to experimental P. aeruginosa corneal infection resulting in corneal perforation (B6) vs. healing (BALB/c). In the proposed studies, multiple approaches will be used and include use of both in vivo and in vitro models to test TLR expression levels, distribution, signaling and immunoregulatory properties. It is expected that the findings will reveal potential targets for early intervention and/or treatment of P. aeruginosa keratitis.