Human susceptibility to Legionella infection

 描述（由申请人提供）：在细胞死亡的背景下，已对胱天蛋白酶进行了充分研究。我们是第一个描述半胱天冬酶的非凋亡功能。我们发表了半胱天冬酶影响吞噬体-溶酶体融合的研究。这个应用程序扩展了我们的研究结果，通过解决的分子机制，胱天蛋白酶-4和-5促进人巨噬细胞囊泡运输。军团菌是一种引起军团菌病的细菌，军团菌病是一种以严重肺炎为特征的人类疾病，死亡率高达30%。军团菌感染那些50岁以上和免疫功能低下。没有疫苗，预防性抗生素不能保护易感人群。因此，了解人类易感的原因将有助于设计未来预防和治疗的新策略。我们发现，在人类巨噬细胞中，含有军团菌的空泡不会与溶酶体融合，而是细菌存活和复制。通常，精确的肌动蛋白聚合和解聚是正确的囊泡运输和吞噬体溶酶体融合所必需的。我们假设军团菌破坏了肌动蛋白聚合机制的功能，以防止溶酶体融合，并建立感染人类巨噬细胞。因此，这一提议将提供一个分子框架，以了解caspase-4和-5有助于先天免疫反应的机制。我们将确定下游效应分子，可以在未来的治疗，以促进军团菌清除靶向。我们拥有人类细胞的专业知识和可用性，这是一个罕见的组合来追求这个新项目。

 DESCRIPTION (provided by applicant): Caspases have been well studied in the context of cell death. We are among the first to describe non-apoptotic functions for caspases. We published that caspases influence phagosome lysosome fusion. This application extends our findings by addressing the molecular mechanism by which caspase-4 and -5 promote vesicular trafficking in human macrophages. Legionella is a bacterium that causes Legionnaires' disease, a human illness characterized by severe pneumonia with fatality rates up to 30%. Legionella infects those above 50 years and the immunocompromised. There is no vaccine and prophylactic antibiotics do not protect the susceptible population. Therefore, understanding why humans are susceptible will help design new strategies for prevention and treatment in the future. We found that in human macrophages, the Legionella-containing vacuole does not fuse with the lysosome and instead the bacteria survives and replicates. Typically, precise actin polymerization and depolymerization are required for proper vesicular trafficking and phagosome lysosome fusion. We hypothesize that Legionella disrupts the function of the actin polymerization machinery to prevent lysosomal fusion and to establish infection in human macrophages. Therefore, this proposal will provide a molecular framework to understand the mechanism by which caspase-4 and -5 contribute to the innate immune response. We will identify downstream effector molecules that can be targeted with therapeutics in the future to promote Legionella clearance. We have the expertise and availability of human cells, which is a rare combination to pursue this novel project.