Neonatal E. coli K1 meningitis is the most common serious infection of the central nervous system with unchanged rates of mortality and morbidity. Survivors of this disease suffer a number of complications including mental retardation and speech impairment. Limited knowledge about the pathogenesis and pathophysiology of this disease hampered the efforts to develop new therapeutic strategies for the prevention. For example, most cases of E. coli K1 meningitis occur via hematogenous spread, but it is unclear how the circulating E. coli evades the host-defense mechanisms. The investigator's studies have shown that outer membrane protein A (OmpA) of E. coli contributes to resistance to serum bactericidal activity. In addition, OmpA interacts with a brain specific 95 kDa receptor for E. coli invasion of the blood-brain barrier (BBB). The E. coli invasion of the BBB was significantly reduced in the presence of adult human serum (AHS) when compared to cord blood serum (CBS) using the investigator's in vitro model of the BBB, the cultured brain microvascular endothelial cells (BMEC). His data further showed that OmpA binds to C4-binding protein, a complement fluid phase regulator, in significant quantities from AHS when compared to CBS. A compelling observation is that the binding of C4-binding protein to OmpA blocked the E. coli invasion of BMEC, suggesting that it is competing with the OmpA-receptor. The investigator hypothesized that binding of C4BP to OmpA blokcs the E. coli invasion of BMEC and that low levlels of C4BP may contribute to the susceptibility of neonates to E. coli meningitis. He will pursue this hypothesis by study of the following specific aims. 1. To determine the binding site of C4BP on OmpA that blocks E. coli invasion of BMEC, and 2. To assess the effect of anti-OmpA antibody, OmpA-peptides, and C4BP-peptides on E. coli invasion of BMEC in the newborn rat model of hematogenous meningitis.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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Special Emphasis Panel (ZHD1-MRG-C (NP))
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Vitkovic, Ljubisa
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Children's Hospital of Los Angeles
Los Angeles
United States
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