MICHELLE C. CALLEGAN, Ph.D. Associate Professor Departments of Ophthalmology, Microbiology & Immunology, and Oklahoma Center for Neuroscience Chair, DMEI Institutional Animal Care and Use Committee Telephone: (405) 271-3674 Fax: (405) 271-8781 Email: michelle-callegan@ouhsc.edu

updated February 2009

The Callegan Lab | Research Interests | Curriculum Vitae and Research Support | Collaborations

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--Present Focus of Research--

--Relevant findings and ongoing research projects--

The murine model of Bacillus endophthalmitis is being used to analyze the acute stage of posterior segment inflammation. The proinflammatory cytokine TNFa is detected in the eye just prior to PMN influx into the posterior segment, suggesting that TNFa may be recruit PMNs to the interior of the eye. TNFa knockouts and anti-TNFa therapeutics are being analyzed to determine the role of TNFa in bacterial endophthalmitis. (Ramadan)

Early changes in retinal function, as measured by electroretinography (ERG), include a stark increase in b-wave latency several hours before the precipitous drop in b-wave amplitude. These findings suggest alteration in the function of cells responsible for the b-wave (i.e. Muller cells) during the early stages of infection. Preliminary results also indicate an early change to a-wave function during infection, suggesting photoreceptor cell dysfunction. By analyzing the effects of infection and toxins on specific retinal cell types we hope to characterize the cellular mechanisms of vision loss during the early stages of infection. (Ramadan)

During the acute stage of inflammation, the blood retinal barrier becomes permeable, resulting in migration of larger molecules and cells into the retina and vitreous. We are analyzing ocular permeability at the level of the retinal pigment epithelium (RPE) to determine whether disruption of tight junctions or cytoskeletal rearrangements within blood retinal barrier contributes to permeability, and what toxins are involved in these events. (Moyer)

Endogenous endophthalmitis (EE) results from metastatic spread of bacteria into the eye from a distant site of infection. Those afflicted by EE tend to be immunocompromised individuals, including elderly diabetics. EE is particularly devastating because it has the capacity to blind bilaterally. We are developing experimental models of EE caused by both Gram-negative and Gram-positive bacteria that will be used to analyze the mechanisms of bacterial migration across the blood ocular barrier and therapies designed to block these events. (Wiskur)

Klebsiella pneumoniae is a devastating pathogen of the eye, most often acquired following pyogenic liver infection in both immunocompetent and immunocompromised individuals. We are presently analyzing the specific virulence factors involved in persistent and systemic infection, prior to migration into the eye (Hunt), and those responsible for migration of Klebsiella across the blood retinal barrier (Wiskur).

No universal therapeutic regimen exists for the treatment of severe bacterial endophthalmitis. Bacillus endophthalmitis is particularly devastating, resulting in blindness or loss of the eye in the majority of cases. We are now testing newer and more potent antibiotics, anti-inflammatory drugs, and earlier drug delivery to improve therapeutic outcomes of Bacillus endophthalmitis. Our results suggest that intravitreal antibiotics should be administered as early as possible to save useful vision, especially if patients suffer from "dirty" penetrating injuries.  (Wiskur)

Bacillus migrates into all parts of the eye within 18 hours. Bacillus strains defective in motility do not migrate within the eye, replicate slower, are defective in toxin production, and cause infections that are highly attenuated for the first 24 hours. Characterization of the attenuation of infection by motility blockade is presently underway. (Callegan)

Components of the Bacillus cell wall incite intraocular inflammation in sterile endophthalmitis models, but do not affect retinal function. Individual bacterial cell wall-associated constituents (i.e. peptidoglycan, teichoic acid, capsules, S-layer) are being analyzed as inducers of acute intraocular inflammation. Bacterial component recognition by retinal cells is being analyzed using toll-like receptor knockout mice. (Novosad)

The role of Bacillus proteases in endophthalmitis has not been determined. Bacillus strains that lack the immune inhibitor metalloproteases InhA and InhA2 are slightly more virulent than their wild type parental strain. Further studies are underway to determine why the absence of these proteases enhances virulence (Hunt/Novosad).

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