The mortality and morbidity associated with neonatal bacterial meningitis have remained significant despite advances in antimicrobial chemotherapy and supportive care. Inadequate knowledge of the pathogenesis and pathophysiology has contributed to this unacceptably high mortality and morbidity. E. coli is the most common gram-negative organism that causes meningitis during the neonatal period. Most cases of E. coli meningitis in newborns develop as a result of hematogenous spread. We have established an infant rat model of experimental hematogenous meningitis which mimics human E. coli infection (e.g. age dependency, hematogenous infection of meninges without the need for adjuvant or direct inoculation of bacteria into cerebrospinal fluid). We have also established as in vitro model of the blood brain barrier using brain microvascular endothelial cells (BMEC). Using these in vitro and in vivo systems, we so far have shown that successful traversal of E. coli across the blood-brain barrier is a complex process involving multiple steps of E. coli-host interactions, e.g., S fimbriae for binding to BMEC, outer membrane protein A and other proteins for invasion into BMEC, and the K1 capsule for protection from killing. Also, we showed that chito-oligomers (specific for wheat germ agglutinin) were able to block the invasion of E. coli into BMEC both in vitro and in vivo suggesting that GIcNAc-14-GlcNAc specific receptors on BMEC interact with E. coli invasion. In addition, we have successfully developed immortalized BMEC cell lines. Based on the resources and findings derived from the past funding period, we should be able to examine the following specific aims: 1. To further elucidate E. coli structures that contribute to invasion of the blood-brain barrier in vitro and in vivo. 2. To identify and characterize (BMEC proteins that are involved in invasion of E. coli. The information derived from this proposal should enhance our understanding of the pathogenesis and prevention of E. coli meningitis.
Showing the most recent 10 out of 103 publications
