Pheromone Signaling in Pneumocystis Carinii

描述（申请人提供）：肺囊虫是一种机会性真菌病原体，可引起艾滋病患者严重肺炎（PCP）。在肺炎期间，肺囊虫通过营养形式和囊肿增殖。调节肺囊虫生命周期的机制尚不明确，但在密切相关的真菌中，信息素诱导的丝裂原活化蛋白激酶（MAPK）信号通路调节了这一过程。我们的研究表明，P. carinii MAPK PCM是真菌信息素MAPK的同源物，在酵母中补充信息素信号。与囊肿相比，在营养形态中PCM的表达和活性大大增强，这意味着PCM活性在肺囊虫生命周期的转变中。我们发现PCM对生化激酶活性有独特的要求，而MAPK功能所需的典型磷酸化位点并不需要PCM激酶活性。这些发现提示了PCM的新调控，其进一步研究可能为病原真菌的信号通路提供见解。此外，我们已经确定了可能的信息素受体和转录因子作为P. carinii MAPK途径的一部分。在本研究中，我们假设信息素诱导的丝裂原活化蛋白激酶（MAPK）途径调节卡氏假单胞菌的细胞分化和增殖。我们将通过三个独立但相互关联的具体目标来研究这些概念。通过这些研究，我们希望进一步了解卡氏假单胞菌的生物学特性，为开发治疗PCP的新药提供新的信息。

DESCRIPTION (provided by applicant): Pneumocystis is an opportunistic fungal pathogen which causes severe pneumonia (PCP) in patients with AIDS. During pneumonia, Pneumocystis proliferates through trophic forms and cysts. Mechanisms regulating the Pneumocystis life cycle are not well defined, however a pheromone-induced mitogen-activated protein kinase (MAPK) signaling pathway regulates this process in closely-related fungi. Our studies demonstrate that the P. carinii MAPK PCM, an ortholog to fungal pheromone MAPKs, complements pheromone signaling in yeast. PCM expression and activity are greatly augmented in trophic forms compared to cysts, implicating PCM activity in Pneumocystis life cycle transition. We have discovered that PCM has unique requirements for biochemical kinase activity, and the typical phosphorylation sites required for MAPK function are not needed for PCM kinase activity. These findings suggest novel regulation of PCM, the further study of which might provide insights into signaling pathways hi pathogenic fungi. Additionally, we have identified putative pheromone receptors and a transcription factor as part of this MAPK pathway in P. carinii. In the current proposal, we hypothesize that the pheromone-induced mitogen-activated protein kinase (MAPK) pathway regulates cellular differentiation and proliferation of P. carinii. We will investigate these concepts through three independent but interrelated Specific Aims. Through these investigations we hope to gain insights into P. carinii biology which may provide new information for novel drug development to treat PCP.