Pheromones and Titan Cell Production in Cryptococcus neoformans

描述(由申请人提供)：信息素和信息素受体很早就知道影响机会致病菌新生隐球菌的毒力，但信息素信号的生物学分支如何影响发病机制仍完全不清楚。尼尔森实验室已经证明，信息素感应改变了一种新的特征细胞类型--被称为“泰坦细胞”--的产生。泰坦细胞的过度生产与中枢神经系统穿透能力的降低有关。这项应用的目的是确定泰坦细胞在发病机制中的作用，以及信息素信号如何改变泰坦细胞的生产。我们应用的中心假设是，信息素信号级联与其他信号成分一起调节泰坦细胞的形成，从而影响随后向中枢神经系统的传播。拟议研究的基本原理是，一旦知道泰坦细胞在发病机制中的作用以及它们是如何调节的，泰坦细胞的生产就可以成为预防和治疗隐球菌病的新的创新方法的靶点。我们计划验证我们的中心假说，并通过追求以下特定目标来实现这一应用的目标：1)确定泰坦细胞在发病机制中的作用；2)确定参与泰坦细胞形成的信号通路。这项研究的预期结果是回答信息素信号为什么影响新生弧菌致病机制这一长期存在的问题，确定泰坦细胞产生在致病中的作用，识别导致泰坦细胞产生的信号，并了解泰坦细胞的形成和复制。这些结果将产生重要的积极影响，因为已确定的对泰坦细胞形成至关重要的信号成分和/或下游靶点有望为帮助艾滋病毒/艾滋病患者的预防性和治疗性干预提供新的靶点。我们希望我们的贡献是详细了解信号转导如何级联调节泰坦细胞的形成，以及泰坦细胞的形成如何影响随后的细胞向中枢神经系统的扩散。这项拟议的研究具有重要意义，因为它有望提供有关泰坦细胞形成、调节和发病机制的知识，这将增强我们对隐球菌疾病的基本要求的理解，并使泰坦细胞成为抗真菌治疗的靶点。 公共卫生相关性：艾滋病患者死亡的一个主要原因是由机会性真菌新生隐球菌引起的脑膜炎。为了减少疾病的流行，我们需要了解这种生物是如何致病的。这一建议研究了形态变化对寄主环境的响应。一旦我们了解了新生葡萄球菌是如何在宿主中生长和存活的，我们就可以开发出阻止这一过程的治疗策略。

DESCRIPTION (provided by applicant): Pheromones and pheromone receptors have long been known to affect virulence of the opportunistic pathogen Cryptococcus neoformans, yet it is still entirely unclear how the biological ramifications of pheromone signaling affect pathogenesis. The Nielsen laboratory has shown that production of a newly characterized cell type - referred to as "titan cells" - is altered by pheromone sensing. Over-production of titan cells is correlated with reduced CNS penetration. The objective of this application is to define the role of titan cells in pathogenesis and how pheromone signaling alters titan cell production. The central hypothesis of our application is that the pheromone signaling cascade, in conjunction with other signaling components, regulates titan cell formation, which affects subsequent dissemination to the CNS. The rationale for the proposed research is that, once the role of titan cells in pathogenesis and how they are regulated is known, titan cell production can be targeted in new and innovative approaches for the prevention and treatment of cryptococcosis. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: 1) Establish the role of titan cells in pathogenesis, and 2) Identify signaling pathways involved in titan cell formation. The expected outcomes of this research are to answer the long-standing question of why pheromone signaling affects pathogenesis in C. neoformans, to define the effect of titan cell production on pathogenesis, to identify signals that lead to titan cell production, and to understand titan cell formation and replication. Such results will have an important positive impact, because identified signaling components and/or downstream targets important for titan cell formation are expected to provide new targets for preventative and therapeutic interventions that will aid HIV/AIDS patients. We expect our contribution to be a detailed understanding of how signal transduction cascades regulate titan cell formation and how titan cell formation affects subsequent cell dissemination to the CNS. The proposed research is significant because it is expected to provide knowledge about titan cell formation, regulation, and pathogenesis that will enhance our understanding of the fundamental requirements for cryptococcal disease and allow titan cells to be targeted by antifungal therapy. PUBLIC HEALTH RELEVANCE: A leading cause of death in AIDS patients is meningitis caused by the opportunistic fungus Cryptococcus neoformans. In order to reduce disease prevalence we need to understand how this organism causes disease. This proposal studies morphological changes in response to the host environment. Once we know how C. neoformans is able to grow and survive in the host, we can develop treatment strategies that block this process.