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Invasion of CNS by L. monocytogenes is one of the main reasons for the 20% to 30% mortality in infected patients. One of the main routes of CNS infection is direct invasion of human brain microvascular endothelial cells (HBMEC) by L. monocytogenes. <P> The overall objective of this application is to understand the first steps in invasion of human brain microvascular endothelial cells by L. monocytogenes. <P>Our expected outputs will be a new understanding of the initial molecular events governing Listeria adherence to, and invasion of, brain microvascular endothelial cells as a route to CNS infection.
NON-TECHNICAL SUMMARY: <BR> Listeria monocytogenes is a foodborne pathogen that causes 20% mortality in infected patients because of its ability to invade the central nervous system (CNS) and other vital organs. Direct invasion of human brain microvascular endothelial cells (HBMEC) is the primary mechanism of CNS infection by L. monocytogenes; however, the underlying molecular pathways are poorly understood. The overall objective is to understand the first steps in invasion of human brain cells by L. monocytogenes. The rationale for the proposed research is to understand the function of invasive-associated surface proteins of L. monocytogenes and its association with CNS endothelial cells in order to bring us one step closer to developing a strategy to prevent bacterial infection. The outcomes of this study are therefore crucial to advance the understanding of CNS invasion mechanism and identify new components that facilitate the host-pathogen interaction. Consequently, such knowledge will be useful in developing an efficacious therapeutic drug or a vaccine against listeriosis.
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APPROACH: <BR> We will analyze all the surface proteins of L. monocytogenes and selected the possible candidate genes and then construct mutant strains by deleting the selected genes. We will compare between mutant strains to a wild type F2365 on its ability to attach and invade human brain microvascular endothelial cells. This knowledge will have a positive impact because it will lay the foundation to generate necessary knowledge for therapeutics to inhibit this first critical state of the most deadly aspect of listeriosis.