Pheromones and Titan Cell Production in Cryptococcus neoformans

信息素和信息素受体长期以来一直被认为影响机会致病菌新型隐球菌的毒力，但信息素信号传导的生物学后果如何影响发病机制仍然完全不清楚。尼尔森实验室已经证明，一种新特征的细胞类型——被称为“泰坦细胞”——的产生是由信息素感知改变的。泰坦细胞的过量产生与中枢神经系统穿透性降低有关。本应用程序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产生。我们的应用的中心假设是信息素信号级联，与其他信号组件一起，调节巨细胞的形成，影响随后的传播到中枢神经系统。这项研究的基本原理是，一旦泰坦细胞在发病机制中的作用以及它们是如何被调节的，泰坦细胞的产生可以在新的和创新的方法中用于预防和治疗隐球菌病。我们计划通过以下具体目标来验证我们的中心假设并实现本应用的目标：1)建立泰坦细胞在发病机制中的作用，2)确定泰坦细胞形成的信号通路。本研究的预期结果是回答长期存在的问题，为什么信息素信号传导影响新生C.的发病机制，确定泰坦细胞的产生对发病机制的影响，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，因为已确定的信号成分和/或对巨细胞形成重要的下游靶标有望为预防和治疗干预提供新的靶标，从而帮助艾滋病毒/艾滋病患者。我们期望我们的贡献是详细了解信号转导级联如何调节巨细胞形成以及巨细胞形成如何影响随后的细胞传播到中枢神经系统。这项拟议的研究意义重大，因为它有望提供有关巨细胞形成、调节和发病机制的知识，从而增强我们对隐球菌疾病基本要求的理解，并使巨细胞成为抗真菌治疗的靶点。

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.