This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 E. coli meningitis remain significant due to incomplete understanding of the pathogenesis of this disease. Escherichia coli K1 is the major cause of neonatal Gram-negative 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. My colleagues and I have shown that cytotoxic necrotizing factor 1 (CNF1) is a major bacterial determinant contributing to E. coli K1 invasion of HBMEC and that laminin receptor (LR) is the cellular receptor for CNF1, which induces host cell actin cytoskeleton rearrangements through activation of RhoGTPases. Further characterization of CNF1-LR interaction suggests that LR plays essential role in CNF1-mediated E. coli K1 internalization into HBMEC, but it is incompletely understood how CNF1-LR interaction modulates actin cytoskeleton rearrangements in HBMEC, resulting in E. coli K1 invasion of HBMEC. Therefore, I hypothesize that E. coli K1 CNF1 interaction with its receptor (LR) triggers downstream signal transduction pathways responsible for actin cytoskeleton rearrangements and, in turn, E. coli K1 entry into HBMEC.
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