The long term objectives of the studies proposed are to determine specific interactions of host cells and macromolecules with bacterial virulence factors, including receptor/adhesin interactions, which together contribute to the pathogenesis of Pseudomonas aeruginosa (PA) ocular infection. Knowledge of such interactions will provide information critical to rational development of therapies which will serve to lessen or prevent bacterial adhesion, colonization, infectivity, corneal inflammation and impaired vision. Two hypotheses will be tested: 1) that adhesions and other colonization factors in addition to pili contribute to binding of PA to host glycoproteins and glycolipids; 2) that host cells such as neutrophils (PMNs) and T lymphocytes are important in the disparate response to PA of aged (1 and 2 year old) vs young adult (37 postnatal day, P) mice.
Specific aims to test the above hypotheses are:
Aim 1. To identify and characterize the nature of corneal epithelial (CEPs) and stromal (SPs) proteins which interact with pilus and non-pilus (flagella, outer membrane proteins, proteases, endotoxin (LPS), exotoxins A and S) bacterial virulence factors. (Hypothesis one).
Aim 2. To determine and characterize the host lipase sensitive receptor(s) and the bacterial adhesion(s) with which it interacts. (Hypothesis one).
Aim 3. To inhibit PA binding to host corneal macromolecules using anti- receptor Mabs topically and systemically. (Hypothesis one).
Aim 4. To determine: A. the nature of the impaired phagocytic function of PMNs from aged vs young adult mice and B. the significance of preliminary data showing that Mab depletion of CD8+ T cells exacerbates disease in both ages of mice and that ocularly infected aged mice (susceptible, S) are unable to mount a delayed type hypersensitivity (DTH) response upon subsequent footpad challenge, while young adult mice (resistant, R) are able to do so (Hypothesis two). To achieve these aims, biochemical, microbiological, immunoelectron microscopic, hybridoma production, and tissue and organ culture methods will be used.
| 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 |
| 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 |
| 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-1? is essential for effective PMN bacterial killing, antimicrobial peptide production and apoptosis in Pseudomonas aeruginosa keratitis. PLoS Pathog 9:e1003457 |
| Berger, Elizabeth A; Vistisen, Kerry S; Barrett, Ronald P et al. (2012) Effects of VIP on corneal reconstitution and homeostasis following Pseudomonas aeruginosa induced keratitis. Invest Ophthalmol Vis Sci 53:7432-9 |
| Jiang, Xiaoyu; McClellan, Sharon A; Barrett, Ronald P et al. (2012) The role of VIP in cornea. Invest Ophthalmol Vis Sci 53:7560-6 |
| Foldenauer, Megan E B; McClellan, Sharon A; Barrett, Ronald P et al. (2012) Substance P affects growth factors in Pseudomonas aeruginosa-infected mouse cornea. Cornea 31:1176-88 |
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