This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite advances in antimicrobial chemotherapy and supportive care, the mortality and morbidity associated with bacterial meningitis remain significant due to incomplete understanding of the pathogenesis of this disease. Escherichia coli K1 is the major cause of neonatal bacterial meningitis and its invasion of human brain microvascular endothelial cells (HBMEC) is a prerequisite for its penetration of blood-brain barrier (BBB) in vivo and in vitro. We have shown that cytotoxic necrotizing factor 1 (CNF1) is a major bacterial determinant contributing to E. coli K1 invasion of HBMEC through interaction with its host receptor, laminin receptor (LR). Further characterization of CNF1-LR interaction suggests that LR plays an essential role in CNF1-mediated E. coli internalization into HBMEC, but it is incompletely understood how CNF1-LR interaction modulates actin cytoskeleton rearrangements in HBMEC, resulting in E. coli invasion of HBMEC. Therefore, I hypothesize that CNF1 interaction with its receptor (LR) triggers downstream signal transduction pathways responsible for actin cytoskeleton rearrangements and, in turn, E. coli entry into HBMEC.
Three specific aims are proposed to (1) determine whether activation of RhoGTPases is a proximal downstream of CNF1-laminin receptor (LR) interaction in HBMEC; (2) determine signaling molecules downstream of RhoGTPases activated through CNF1-LR interaction; (3) determine the role of ezrin in CNF1-mediated E. coli invasion of HBMEC. The information derived from this study should enhance our understanding of the pathogenesis of E. coli meningitis, i.e., molecular mechanisms underlying CNF1-mediated E. coli internalization into HBMEC and lead to the development of novel strategies to prevent E. coli meningitis.
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