Phillip S. Coburn, PhD
Assistant Professor of Research, Department of Ophthalmology
- Vascular Permeability and Development of Endogenous Bacterial Endophthalmitis
- Pathogenesis of Enterococcus Faecalis Endophthalmitis
- Nanotherapeutics For Bacterial Ocular Infections
- Transcriptomics of Bacterial Ocular Infections
- PhD: Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Postdoctoral Training: Departments of Pharmaceutical Sciences and Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK
Endophthalmitis is a serious, sight-threatening infection of the posterior segment of the eye. The vast majority of cases result from intraocular surgical procedures.
Over the past several decades, the number of post-operative endophthalmitis cases has risen steadily, owing to the increase in the number of invasive ocular surgeries performed. Filtering bleb-associated endophthalmitis results from the introduction of organisms into the conjunctival filtering bleb following a trabeculectomy. The frequency of this type of endophthalmitis has been reported to be as high as 10% of glaucoma filtering procedures and is continuing to rise with the increase in use of the antifibrotic agents.
The bacterium Enterococcus faecalis is responsible for 4–8% of cases of postoperative endophthalmitis and is frequently isolated from infected filtering blebs. These infections can represent a therapeutic challenge due to the emergence of multi-drug resistant strains of E. faecalis. Our research involves the identification and characterization of E. faecalis factors that contribute to endophthalmitis, and the analyses of retinal function and the inflammatory response in eyes infected with E. faecalis strains that differ in the production of various virulence factors. We are also studying the mechanisms involved in blood-ocular barrier permeability during infection, and the role of diabetes in bloodstream-to-eye spread of bacteria.
Based on these studies, we are developing novel target-based therapeutics to be used with antibiotics, anti-inflammatory, and surgical regimens in order to preserve vision during this blinding disease. Our research program provides instructional backgrounds, mastery of techniques, and publications in the areas of ophthalmology, microbiology, immunology, and vision neuroscience.
Phillip Coburn has a broad background in microbiology and molecular biology, with specific training and expertise in bacterial genetics, mechanisms of action of bacterial protein toxins, bacterial gene regulation, and a wide range of murine infection models. His graduate training primarily consisted of characterizing a broad-spectrum, two-component toxin, termed cytolysin, that is produced by virulent strains of Enterococcus faecalis. The E. faecalis cytolysin is a unique, two-peptide lytic toxin that has evolved multiple activities in a single system.
Coburn’s most important contribution during this period was the description of the role of the larger of the two peptides, CylLL”, in the regulation of cytolysin expression. This peptide is used by E. faecalis as a means for detecting target cells in the vicinity of the bacterium and triggering high-level cytolysin expression only when target cells are present. This seminal study was published in the journal Science (1). In addition, he examined the structure/activity relationships of the CylLS” subunit by alanine scanning mutagenesis. He found that no amino acid within the mature sequence of CylLS” was dispensable for all activities. However, he did demonstrate that hemolytic, antibacterial, and signaling activities are separable activities, and showed that CylLS” is precisely honed to maintain a balance between activity against eukaryotic cells and suicidal production due to increased bacteriocin activity, and/or indirectly due to increased production from greater signaling capacity.
Just prior to beginning his postdoctoral training in the Department of Pharmaceutical Sciences at OUHSC, Cobun’s postdoctoral mentor, Dr. Nathan Shankar, identified a pathogenicity island (PAI) in a hospital ward outbreak strain of E. faecalis. This PAI was shown to possess genes encoding a number of well-characterized E. faecalis virulence factors, as well as genes that have been hypothesized to be advantageous in GI tract colonization. While in his lab, Coburn demonstrated that the PAI is enriched among virulent, infection-derived isolates of E. faecalis, and that portions of the PAI can be mobilized and transferred both in vitro and during transient colonization of the GI tract (2). Further, he secured funding from the American Heart Association to explore the role of a new member of the AraC-type transcriptional regulators encoded on the PAI, designated PerA, in E. faecalis pathogenesis. In that study, Coburn’s major goal was to determine whether PerA contributes directly to causing disease and to identify genes, that also might be involved in disease, that are controlled by this protein. His findings were published in Infection and Immunity and PLoS One (3,4). During this period, he expanded his repertoire of molecular and biochemical techniques such as protein purification, gel-shift and DNase footprinting assays for promoter mapping, gene expression profiling by microarray analysis, and a murine intraperitoneal model of E. faecalis infection.
After successfully completing this training period, Coburn decided it was time for a major shift in his career goals and to pursue another area of research. After working in the area of bacterial genetics and molecular biology for 14 years, the prospect of undertaking new challenges and developing additional skills and capabilities was an exciting one, particularly the opportunity to work with a leader in the field of pathogenesis and chemotherapy of bacterial ocular infections, Michelle Callegan. As a postdoctoral fellow in Dr. Callegan’s laboratory, he explored the influence of changes in vascular permeability within the eye during the development of diabetes on the occurrence of endogenous bacterial endophthalmitis (EBE) in a mouse model of streptozotocin-induced diabetes that he helped develop. Using this model, Coburn demonstrated a correlation between the duration of diabetes and incidence of Klebsiella pneumoniae EBE and also showed that increases in vascular permeability within the eye may contribute to the enhanced rate of K. pneumoniae EBE (5).
In the summer of 2011, Coburn secured a faculty appointment in the Department of Ophthalmology at OUHSC. He began developing his own research program that is primarily focused on identifying mechanisms by which Enterococcus faecalis causes ocular infections, exploring the pathogenic mechanisms of S. aureus and K. pneumoniae EBE, and evaluating the effectiveness of a novel biomimetic nanosponge as an adjunct therapy for detoxification of ocular infections caused by pathogens that produce pore-forming toxins.
Mursalin, MH., P.S. Coburn, E. Livingston, F.C. Miller, R. Astley, A. Fouet, and M.C. Callegan. 2019. S-layer impacts the virulence of Bacillus in endophthalmitis. Invest. Ophthalmol. Vis. Sci. 60:3727-3739.
Baldwin, J., D. Keith, GT Dolan, V. Grantham, P.S. Coburn, and W. Galbraith. 2019. Residual blood, mold, and bacterial contamination in nuclear pharmacy lead unit dose containers following a common disinfection method. J. Am. Pharm. Assoc. 59(4):e38-e250.
Astley, R., F.C. Miller, M.H. Mursalin, P.S. Coburn, and M.C. Callegan. 2019. An eye on Staphylococcus aureus toxins: roles in ocular damage and inflammation. Toxins (Basel). 2019 Jun 19;11(6). doi: 10.3390/toxins11060356.
Miller, F.C., P.S. Coburn, M.M. Huzzatul, A.L. LaGrow, E. Livingston, and M.C. Callegan. 2019. Targets of immunomodulation in bacterial endophthalmitis. Prog. Retin. Eye Res. 2019 May 28. pii: S1350-9462(19)30027-8. doi: 10.1016/j.preteyeres.2019.05.004. [Epub ahead of print] Review. PubMed PMID: 31150824.
Coburn, P.S., F.C. Miller, A.L. LaGrow, C. Land, H. Mursalin, E. Livingston, O. Amayem, Y. Chen, W. Gao, L. Zhang, and M.C. Callegan. 2019. Disarming pore-forming toxins with biomimetic nanosponges in intraocular infections. mSphere 4:e00262-19. https://doi.org/10.1128/mSphere.00262-19.
Coburn, P.S., F.C. Miller, A.L. LaGrow, S.M. Parkunan, C.B. Randall, R.L. Staats, and M.C. Callegan. 2018. TLR4 modulates inflammatory gene targets in the retina during Bacillus cereus endophthalmitis. BMC Ophthalmol. Apr 16;18(1):96. doi:10.1186/s12886-018-0764-8.
LaGrow, A.L., P.S. Coburn, F.C. Miller, C. Land, S.M. Parkunan, B.T. Luk, W. Gao, L. Zhang, and M.C. Callegan. 2017. A novel biomimetic nanosponge protects the retina from the Enterococcus faecalis Cytolysin. mSphere. 2(6). pii: e00335-17. doi:10.1128/mSphere.00335-17. eCollection 2017 Nov-Dec.
Callegan, M.C., S.M. Parkunan, C.B. Randall, P.S. Coburn, F.C. Miller, A.L. LaGrow, R.A. Astley, C. Land, S. Oh, O. Schneewind. 2017. The role of pili in Bacillus cereus intraocular infection. Exp. Eye Res. 159:69-76.