Leukocyte Transmigration in Neonatal Candida Meningitis

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DESCRIPTION (provided by applicant): Neonatal meningitis produced by opportunistic pathogenic microorganisms such as the yeast Candida albicans is an inflammatory condition that can occur during the first month after birth and is a leading cause of neurodegenerative states and morbidity in premature and immunocompromised infants. Meningitis in neonates is attributable to the incomplete development of the CNS, the blood-brain barrier (BBB) and the immune system. The precise nature of adhesion and transmigration of pathogenic organisms and leukocytes across the BBB during inflammatory conditions remains unclear and is an issue of great interest in modern medicine. This research program will focus at the mechanisms of adhesion and transmigration of C. albicans and inflammatory leukocytes that appear in response to the microorganisms during the process of meningitis. Our study will be conducted in an in vivo model of experimentally induced meningitis in neonatal rats. Our hypothesis states that the pathogenic yeast C. albicans initially induce the inflammatory state in the meningeal blood vessels. Subsequently, leukocytes adhere to and traverse the endothelial cell (EC) barrier stimulated by the local release of chemoattractant substances in response to the yeast cells. The entire process of adhesion and transmigration across the BBB is facilitated by adhesion molecules including ICAM-1, PECAM-1 and VCAM-1 either across the ECs by a transcellular pathway, through EC junctional complexes by a paracellular pathway, or by both mechanisms. Our specific aim of the project will be to define and compare the light microscopic, immunohistochemical, ultrastructural and immunoultrastructural nature of adhesion and transmigration of a virulent strain of C. albicans, and the different major subsets of inflammatory leukocytes including neutrophils, mononuclear cells and lymphocytes that appear in response to the yeast-induced meningoencephalitis in neonatal rats. This will lay the groundwork for us to investigate how adhesion molecules regulate the attachment and transmigration of pathogenic yeast cells and leukocytes across the BBB via specialized anatomical "gateways to the brain" through either modified EC conduit-like structures, open EC junctional complexes or by both pathways. Such studies will hopefully establish a framework that may lead to the development of therapeutic intervention for the treatment of neonatal meningitis and several other inflammatory conditions of the CNS.