OMIG, Thygeson Lecture
Main Page | 2004
aeruginosa: Models and Treatment of the Disease
Linda D. Hazlett, Ph.D.
Pseudomonas aeruginosa is a common organism associated
with bacterial keratitis, especially in extended wear contact lens
users. Advances in our understanding of host innate and adaptive
immune responses to experimental infection have been made using
inbred murine models that are classed as resistant (cornea heals)
vs. susceptible (cornea perforates).
Methods: A variety of immunological, microbiological,
molecular and statistical analyses and approaches were used.
Results: Data provide evidence that sustained IL-12
driven IFN-γ production in dominant Th1 responder mouse strains
such as C57BL/6 (B6) contributes to corneal destruction and perforation,
while IL-18 driven production of IFN-γ (by NK cells) in the
absence of IL-12 p40, is associated with bacterial killing and less
corneal destruction in dominant Th2 responder strains such as BALB/c.
Data also suggest that IFN-γ contributes to bacterial killing
indirectly by regulating macrophage nitric oxide levels in cornea.
The critical role of PMN in the innate response to bacterial infection
will be discussed, as mice of either strain depleted of PMN and
then infected, die within 48 hours. Regulation of PMN will be discussed
and evidence from antibody neutralization experiments provided to
show that persistence of PMN in B6 cornea is regulated by CD4+ T
cells, while macrophages (and NK cells) regulate PMN number in the
cornea of BALB/c mice. The importance of IL-1 and its neutralization
or inhibition (caspase-1 inhibitor) will be discussed as a novel
adjunctive treatment for bacterial keratitis.
Conclusions: These studies continue to provide
better understanding of the inflammatory mechanisms that are operative
in the cornea after P. aeruginosa challenge and are consistent
with our long-term goals of providing targets for alternative or
adjunctive treatment for this disease.
commercial relationships. Grant support: NIH R01EY02986 and P30EY04068.
Main Page | 2004