LISTERIA PROTEINS EFFECTS ON CELL FUNCTION

描述(改编自申请者摘要)：李斯特氏菌 单核细胞增多症(LM)是一种广泛存在的食源性病原体，与 周期性的疾病爆发，导致胃肠道疾病，败血症， 在某些情况下，致命的脑膜炎。李斯特菌病通常与 一种免疫受损的状态，在艾滋病患者中，这种情况发生在 大约是在非艾滋病人群中发现的300倍。 LM被包括巨噬细胞在内的不同细胞摄取。vt.在.的基础上 通过巨噬细胞的内化，细菌可能有两种可能的命运： (1)它可以逃逸到细胞质中，在那里它可以复制，随后 侵入其他细胞；(2)它留在吞噬小泡内，是 被杀了。他们已经获得了初步证据，表明 通向这两种可能结果之一的路径由 细菌进入巨噬细胞的方式。如果通过以下方式使用LM 第三补体成分(CR3)的受体，它不会逃脱 进入细胞质并被杀死。如果LM通过结合巨噬细胞进入巨噬细胞 细菌内毒素A(INLA)分子与未知表面的结合 巨噬细胞上的分子，细菌逃逸到细胞质中， 复制。通过与其他细菌的吸收类比，很可能 与细胞表面受体相关的信号转导事件 当LM与巨噬细胞结合时，分子被启动。 在这项提议中，他们将进行实验，以检验以下假设 通过INLA与其受体相互作用进入巨噬细胞的LM 不会被巨噬细胞杀死。首先，他们将定义 链球菌素A对金黄色葡萄球菌的结合、吞噬和杀灭作用 非抗李斯特菌巨噬细胞。其次，他们将描绘出分子 Lm In1a与其相互作用引起的巨噬细胞内的事件 推测是巨噬细胞受体。它们将定义信号转导 在LM与推定的In1a受体结合后发生的事件， 并将它们与在将LM绑定到CR3时启动的事件进行比较。第三，他们 将尝试鉴定、鉴定和分离In1a受体。这些 实验应该提供关于LM相互作用的有价值的信息 与吞噬细胞结合，并可能提供对吞噬作用和 杀死其他细胞内细菌。

DESCRIPTION (Adapted from applicant's abstract): 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.