The mortality and morbidity associated with neonatal bacterial meningitis have remained significant despite advances in antimicrobial chemotherapy and supportive care. Escherichia coli is the most common Gram-negative organism that causes meningitis during the neonatal period. Both clinical and experimental data indicate limited efficacy with antimicrobial chemotheraphy alone. A search for other therapeutic approaches (e.g. immunotherapy) to these infection is limited by the inadequate knowledge of the pathogenesis and pathophysiology associated with bacterial entry into the cerebral nervous system. The applicant has established an infant rat model of E. coli bacteremia and meningitis which has important similarities to human E. coli infection (e.g., age dependency, hematogenous infection of the meninges without the need for adjuvant or direct inoculation of bacteria into cerebro-spinal fluid) and also an in vitro model of the blood-brain barrier using cerebral endothelial cells. In addition, the applicant have secured a collection of E. coli strains processing different surface characteristics and a battery of specific antibodies. Using the in vitro and in vivo systems and resources, the applicant should be able to examine the following aims: 1) To study the in vitro system of the blood-brain barrier using endothelial cells of neural and non-neural origin and astrocytes. 2) To evaluate microbial facts (capsule, lipopolysaccharide, LPS, and S. fimbriae) in the development of E. coli meningitis. 3) To further understand the interaction of host-microbial factors responsible for the development of E. coli bacteremia and meningitis. The information derived from this proposal should enhance our understanding of the pathogenesis, prevention and therapy of bacterial meningitis in newborns and children.
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