Endophthalmitis is a sight-threatening infection of the interior of the eye resulting from the introduction of organisms into the posterior segment. Severe endophthalmitis often results in irreversible damage to delicate cells of the retina and explosive intraocular inflammation, ultimately resulting in vision loss. Despite aggressive antibiotic, anti-inflammatory, and surgical treatment, significant vision is lost, if not the entire eye itself, in a very short period of time. The regularity of treatment failures highlights the need for identification and characterization of the deleterious mechanisms involved in endophthalmitis pathogenesis and significant improvements in existing treatment regimens. Rapid vision loss and severe inflammation is common in endophthalmitis caused by B. cereus, one of the most virulent bacterial ocular pathogens. Our previous research centered on the bacterial virulence factors important to infection. The following virulence factors were found to be responsible for the explosive nature of B. cereus endophthalmitis: 1) the highly inflammatory cell wall, 2) toxins regulated by quorum sensing, and 3) the migration of B. cereus throughout all parts of the eye during infection. These bacterial virulence factors represent important potential targets for therapeutic intervention. This competing renewal focuses on the molecular and cellular interactions between B. cereus and the host, highlighting the host response to infection. An experimental mouse model of endophthalmitis was developed for use in these studies, facilitating the characterization of the host-specific cellular and molecular mechanisms involved in pathogenesis. We propose to examine the interactions between toll-like receptors (TLRs) and B. cereus ligands in facilitating intraocular inflammation during endophthalmitis using knockout mice lacking these innate immune receptors. We also propose to analyze the direct and indirect mechanisms of blood-retinal barrier breakdown leading to influx of inflammatory cells and mediators into the posterior segment during endophthalmitis, focusing specifically on the integrity of the retinal pigment epithelial and endothelial barriers during infection. These studies are a logical outgrowth of our current research program, and as such will greatly advance our long-term goal of understanding the pathogenic mechanisms of disease and developing successful treatment strategies for the preservation of vision during endophthalmitis.

Public Health Relevance

Endophthalmitis is a potentially blinding bacterial infection that is often refractory to treatment because of the explosive nature of the infection. The regularity of treatment failures highlights the critical need for significant improvements in existing therapeutic regimens. By identifying the bacterial and host factors important in disease, we can exploit these targets for the development of new treatment strategies that will increase the likelihood of preventing blindness following endophthalmitis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY012985-12S1
Application #
8516632
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2000-06-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
12
Fiscal Year
2012
Total Cost
$176,633
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Astley, Roger A; Coburn, Phillip S; Parkunan, Salai Madhumathi et al. (2016) Modeling intraocular bacterial infections. Prog Retin Eye Res 54:30-48
Parkunan, Salai Madhumathi; Randall, C Blake; Astley, Roger A et al. (2016) CXCL1, but not IL-6, significantly impacts intraocular inflammation during infection. J Leukoc Biol 100:1125-1134
Coburn, Phillip S; Wiskur, Brandt J; Astley, Roger A et al. (2015) Blood-Retinal Barrier Compromise and Endogenous Staphylococcus aureus Endophthalmitis. Invest Ophthalmol Vis Sci 56:7303-11
Parkunan, Salai Madhumathi; Randall, C Blake; Coburn, Phillip S et al. (2015) Unexpected Roles for Toll-Like Receptor 4 and TRIF in Intraocular Infection with Gram-Positive Bacteria. Infect Immun 83:3926-36
Hunt, Jonathan J; Astley, Roger; Wheatley, Nanette et al. (2014) TLR4 contributes to the host response to Klebsiella intraocular infection. Curr Eye Res 39:790-802
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Coburn, Phillip S; Wiskur, Brandt J; Christy, Elizabeth et al. (2012) The diabetic ocular environment facilitates the development of endogenous bacterial endophthalmitis. Invest Ophthalmol Vis Sci 53:7426-31
Novosad, Billy D; Astley, Roger A; Callegan, Michelle C (2011) Role of Toll-like receptor (TLR) 2 in experimental Bacillus cereus endophthalmitis. PLoS One 6:e28619
Hunt, Jonathan J; Wang, Jin-Town; Callegan, Michelle C (2011) Contribution of mucoviscosity-associated gene A (magA) to virulence in experimental Klebsiella pneumoniae endophthalmitis. Invest Ophthalmol Vis Sci 52:6860-6

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