Pseudomonas aeruginosa (P. aeurginosa) is a common opportunistic pathogen which causes bacterial keratitis, especially in contact lens usage (25,000-30,000 cases annually with treatment estimated at $15-30 million). The goal of the studies proposed is to determine the mechanisms involved in development of bacterial keratitis, especially the role of high mobility group box 1 (HMGB1), a prototypic alarmin. HMGB1 is a member of a family of danger associated molecular patterns (DAMPS), a mediator of the systemic inflammatory response syndrome, is elevated late in bacterial infection/sepsis and considered a target for disease treatment. Given that it is important in innate immunity, has different functions dependent on cellular localization, and has the ability to bind to Toll-like-receptors (TLR) and other molecules such as receptor for advanced glycation end products (RAGE), we hypothesize and provide preliminary supportive data, that it has significant amplification effects on the corneal inflammatory cell response and is an important therapeutic target in P. aeruginosa keratitis. Experiments described in this competitive renewal are a logical segue from the currently funded studies on TLR4, as we will focus on HMGB1, a molecule which interacts with TLR ligands and cytokines and activates cells through multiple surface receptors including TLR2, 4 and RAGE. Although HMGB1 is a well- studied member of a family of DAMPS, no information on its role in the infected cornea is available. Thus, how HMGB1 may set the stage, amplify the host immune response and is a target for treatment, will be determined in P. aeruginosa corneal infection.
Two aims are proposed.
Specific Aim 1 : Will test the hypothesis that HMGB1 amplifies corneal inflammation and modulates the effector function of resident and infiltrating cells in bacterial keratitis.
Specific Aim 2 : Will test the hypothesis that HMGB1 is a novel target for treatment and has clinical relevancy. The work is of relevance to human health and has considerable medical and economic impact.
Pseudomonas aeruginosa is a bacterial pathogen which causes corneal disease, especially in extended wear contact lens users. Elucidating the precise role of a host danger signaling molecule (called high-mobility group box 1) in this disease, including how it amplifies corneal inflammation, regulates the function of resident and infiltratin cells and is a novel target for treatment with anti-inflammatory agents, will provide much insight into the pathogenesis of this disease. Ultimately, findings from this proposal will be useful clinically in development of better treatments to reduce disease and prevent blindness.
|Muraleedharan, Chithra K; McClellan, Sharon A; Barrett, Ronald P et al. (2016) Inactivation of the miR-183/96/182 Cluster Decreases the Severity of Pseudomonas aeruginosa-Induced Keratitis. Invest Ophthalmol Vis Sci 57:1506-17|
|Ekanayaka, Sandamali A; McClellan, Sharon A; Barrett, Ronald P et al. (2016) Glycyrrhizin Reduces HMGB1 and Bacterial Load in Pseudomonas aeruginosa Keratitis. Invest Ophthalmol Vis Sci 57:5799-5809|
|McClellan, Sharon; Jiang, Xiaoyu; Barrett, Ronald et al. (2015) High-mobility group box 1: a novel target for treatment of Pseudomonas aeruginosa keratitis. J Immunol 194:1776-87|
|McClellan, Sharon A; Ekanayaka, Sandamali A; Li, Cui et al. (2015) Thrombomodulin Protects Against Bacterial Keratitis, Is Anti-Inflammatory, but Not Angiogenic. Invest Ophthalmol Vis Sci 56:8091-100|
|Jiang, Xiaoyu; McClellan, Sharon A; Barrett, Ronald et al. (2014) HGF signaling impacts severity of Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 55:2180-90|
|Li, Cui; McClellan, Sharon A; Barrett, Ronald et al. (2014) Interleukin 17 regulates Mer tyrosine kinase-positive cells in Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 55:6886-900|
|Hazlett, Linda D; Jiang, Xiaoyu; McClellan, Sharon A (2014) IL-10 function, regulation, and in bacterial keratitis. J Ocul Pharmacol Ther 30:373-80|
|Foldenauer, Megan E B; McClellan, Sharon A; Berger, Elizabeth A et al. (2013) Mammalian target of rapamycin regulates IL-10 and resistance to Pseudomonas aeruginosa corneal infection. J Immunol 190:5649-58|
|Berger, Elizabeth A; McClellan, Sharon A; Vistisen, Kerry S et al. (2013) HIF-1Î± is essential for effective PMN bacterial killing, antimicrobial peptide production and apoptosis in Pseudomonas aeruginosa keratitis. PLoS Pathog 9:e1003457|
|Jiang, Xiaoyu; McClellan, Sharon A; Barrett, Ronald P et al. (2012) The role of VIP in cornea. Invest Ophthalmol Vis Sci 53:7560-6|
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