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Richard J. O'Callaghan,
Ph.D. |
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Professor and Chair of the Department
of Microbiology
Ph.D., University of Mississippi Medical Center
Primary Research Interest:
There are two prime objectives of our research:
1. We use the
eye as a model of infection to discover the virulence mechanisms
of bacteria and the interaction of bacteria and host defenses;
the eye is a precise and unique model that allows repeated observations
of the ongoing infectious process.
2. We seek findings that will help in the prevention and/or treatment
of eye infections, especially in terms of arresting tissue damage.
Our studies of experimental bacterial keratitis in the rabbit have shown
that once bacteria reach a million colony forming units per cornea,
the pathogenic processes initiated by bacterial products cannot be
reversed by the administration of fortified antibiotics alone or in
combination with antiinflammatory drugs. Bacterial toxins and/or enzymes
released into the cornea cause damage directly and they stimulate neutrophil
infiltration causing more damage. The result of keratitis is irreversible
scarring and a loss in visual acuity or even blindness. Thus, there
is a need for new therapies designed to arrest damage as antibiotic
therapy kills the bacteria, a benefit that no presently available drugs
can offer. The development of such therapy requires a full understanding
of the bacterial products that mediate the damage. Underway are bacterial
genetic and biochemical studies to identify such reactive molecules
and to seek chemotherapeutic or immunological means to arrest their
action. These studies are designed to improve therapy of eye infections
and the research employs experimental models particularly well suited
to detect and analyze new aspects of bacterial virulence.
The major ongoing components of this research include:
1. The toxins and the host defense system of the eye are being studied
in Staphylococcus aureus keratitis, a project funded by a RO1 NIH grant.
Among the accomplishments of this research has been the molecular and
biochemical characterization of alpha-toxin in keratitis, use of antibody
to inhibit these reactions, information on production of a new toxin,
and a detailed description of a key host defense of the tear film against
Staphylococcus infection.
2. The role of proteases in Pseudomonas aeruginosa keratitis is also
a major project funded by a RO1 NIH grant. This research led to the discovery
of protease IV, a proven virulence factor and only protease made by all
strains of P. aeruginosa. This research has provided the characterization
of protease IV as an enzyme, protein and virulence factor. Emerging from
this research is a system for expressing various genes of P. aeruginosa
in a non-ocular species to quantify the amount of virulence afforded
by a specific gene product, especially the proteases of this bacterium.
An important aspect of this research is the very recent discovery of
a previously unrecognized protease and the demonstration of its ability
to damage the cornea.
Our research also includes the study of anti-microbial agents in treating
and preventing infections. Important to the antibiotic research are new
antibiotics as well as the development of new formulations that better
deliver drugs to the eye. Animal models of keratitis suitable for quantifying
the effectiveness of antibiotic therapy have been developed for Pseudomonas
aeruginosa, Serratia marcescens, Staphylococcus aureus, and Mycobacterium
chelonae. A model for studying the benefits of antibiotic prophylaxis
has also been developed and used to quantify the value of specific formulations.
Other Activities (last five years)
Program Committee for the Association for Research in Vision and Ophthalmology,
2000-2003, Chairman in 2002-2003.
Selected as the organizer of a symposium entitled "Immunity and
Mechanisms of Ocular Infections" for the Association for Research
in Vision and Ophthalmology, May 2003.
Member of the American Society for Biochemistry and Molecular Biology,
2003-present.
Member of the American Society for Microbiology, 1965-present.
Member of the Association for Research in Vision and Ophthalmology, 1992-present.
NIH Study Section, National Eye Institute, 2002, 2004-present.
Reviewer and Guest Editor for Investigative Ophthalmology and Visual
Sciences, 1997-present.
Reviewer for Current Eye Research, 1998-present.
Reviewer for Cornea, 2002-present.
Reviewer for Ocular Immunology and Inflammation, 2003-present.
Publications:
See attached CV
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