The bacterium Listeria monocytogenes (LM) is a widespread, food borne pathogen that is responsible for periodic outbreaks of disease, causing gastrointestinal disease, sepsis, and in some cases, fatal meningitis. Listeriosis is often associated with an immunocompromised state, and in AIDS patients, it occurs at an incidence approximately 300 times greater than that found in the non-AIDS population. LM is taken up by different cells including macrophages. Upon internalization by macrophages, the bacterium can have two possible fates: (1) It can escape into the cytoplasm where it can replicate and subsequently invade other cells; (2) It remains within a phagocytic vesicle and is killed. They have obtained preliminary evidence which suggests that the pathway leading to either of these two possible outcomes is dictated by the mode of entry of the bacterium into the macrophage. If LM is taken up via the receptor for the third complement component (CR3), it does not escape into the cytoplasm and is killed. If LM enters a macrophage by binding of the bacterial internalin A (InlA) molecule to an as-yet unidentified surface molecule on the macrophage, the bacterium escapes into the cytoplasm and replicates. By analogy to the uptake of other bacteria, it is likely that the signal transduction events associated with the cell surface receptor molecules are initiated upon binding of LM to the macrophage. In this proposal they will conduct experiments to test the hypothesis that LM that enter a macrophage via interaction between InlA and its receptor will not be killed by the macrophage. First, they will define the role of In1A in binding, phagocytosis, and killing of LM by listericidal versus nonlistericidal macrophages. Second, they will delineate the molecular events within macrophages resulting from interaction between LM In1A and its putative macrophage receptor. They will define the signal transduction events which occur following binding of LM to the putative In1A receptor, and compare them to events initiated upon binding of LM to CR3. Third, they will attempt to identify, characterize and isolate the In1A receptor. These experiments should provide valuable information on the interaction of LM with phagocytic cells and may provide insights into the phagocytosis and killing of other intracellular bacteria.
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