Deciphering ubiquitin-regulated host responses to the intracellular pathogen Legi

描述（由申请人提供）：区分致病性和非致病性微生物对宿主免疫系统提出了一个有趣的挑战，对于引发适当的免疫反应来对抗入侵的病原体至关重要。液泡病原体已经进化出多种策略来操纵宿主功能以促进细胞内生存，这就需要免疫分子感觉网络的共同进化，以检测病原体的颠覆企图。为了剖析这一过程是如何在分子水平上发生的，我们开发了一种方法，可以监测宿主蛋白的修饰，从而在计算机上对宿主对致病性感染的反应网络进行逆向工程。为此，我们使用呼吸道病原体嗜肺军团菌作为模式生物来破译宿主细胞途径对致病性挑战的特定调节。该项目的总体目标是使用生化和分子方法来表征巨噬细胞中的细胞通路如何利用调控分子修饰，如泛素，特异性地改变反应致病性感染的信号级联的结果。特别强调的是细胞级联，协调先天免疫细胞的细胞因子反应。

DESCRIPTION (provided by applicant): Distinguishing pathogenic from non-pathogenic microbes presents an interesting challenge to the host immune system and is critical for eliciting the appropriate immune response to combat the invading pathogen. Vacuolar pathogens have evolved multiple strategies to manipulate host functions to promote intracellular survival, necessitating co-evolution of immune molecular sensory networks that detect the pathogen attempts at subversion. To dissect how this process occurs at the molecular level we have developed methodology that monitors modifications on host proteins to reverse-engineer the host response networks to pathogenic infection in silico. To this end, we are using the respiratory pathogen Legionella pneumophila as a model organism to decipher specific regulation of host cellular pathways to pathogenic challenge. The overall goal of the project is to use biochemical and molecular approaches to characterize how cellular pathways in macrophages utilize regulatory molecular modifications, such as ubiquitin, to specifically alter the outcome of signaling cascades in response pathogenic infection. Specific emphasis is placed on the cellular cascades that coordinate the cytokine response of innate immune cells.