Impact of Cryptococcus Titan Cells on Pathogenesis.

项目总结 据估计，侵袭性真菌感染每年导致150万人死亡，其中包括隐球菌 新生杆菌(CN)感染导致的死亡几乎占所有真菌感染死亡的一半。CN在健康人群中很少见 这表明免疫系统能够预防疾病。然而，临床观察到的高死亡率 这表明目前的抗真菌药物治疗对免疫功能低下的人来说是不够的。这一悖论 这表明我们缺少了CN与宿主相互作用的关键组成部分。隐球菌细胞的特性研究 研究表明，CN在感染过程中会产生一种独特的细胞类型--称为“泰坦细胞” 这会改变宿主与病原体的相互作用。这些泰坦细胞是为了响应宿主肺 比一般大小的CN细胞大5-10倍。 我们以前证明过，泰坦细胞的生产对毒力至关重要，并影响传播到 中枢神经系统。我们进一步表明，泰坦细胞的形成通过减少吞噬和刺激来改变宿主的反应 一种有害的Th2介导的反应。病原体和它们的人类宿主之间的相互作用可能非常 复杂，结果取决于宿主和病原体的反应。宿主必须感觉到病原体 相关分子模式(PAMP)，然后产生适当的免疫反应来杀死 病原体。相反，病原体必须感知并对宿主环境做出反应，以促进其自身 生死存亡。这项提议旨在确定泰坦细胞的起源所涉及的关键变化及其 以及定义它们独特的细胞结构如何影响宿主的免疫反应，从而， 发病机制。 泰坦细胞有许多独特的特征，因此我们建议的调查重点是 确定这些特性如何影响：1)病原体在宿主中的适应/存活，以及2)PAMP的变化 被宿主的免疫反应所识别。我们之前的研究表明泰坦细胞经历了倍体变化 与它们的形成和复制有关，并引导我们假设这些变化对 在宿主环境中的适应和生存。因此，我们的第一个目标是定义细胞周期调节 需要产生泰坦细胞和他们的后代。在我们的第二个目标中，我们将测试假设 泰坦细胞壁的变化影响宿主对PAMP的识别，第三个目的决定了这一点 感知的改变产生了对泰坦细胞的有害免疫反应。 这些研究最终将合并成多方面的抗菌疗法，结合靶向病理- 限制病原体适应和调节宿主免疫反应的基因特异性过程，以最大限度地提高 有益的宿主反应，以减少疾病。

PROJECT SUMMARY Invasive fungal infections are estimated to kill one and a half million people annually, with Cryptococcus neoformans (Cn) infection resulting in almost half of all deaths due to fungal infection. Cn is rare in healthy individuals, suggesting the immune system is able to prevent disease. Yet the high mortality observed clinically suggests current antifungal drug treatments are inadequate in immunocompromised individuals. This paradox suggests we are missing critical components of the Cn-host interaction. Characterization of cryptococcal cells during infection has revealed that Cn produces a unique cell type - referred to as “titan cells” - during infection that alter the host-pathogen interaction. These titan cells are produced in response to the host pulmonary environment and are 5-10x larger than typical-sized Cn cells. We demonstrated previously that titan cell production is critical for virulence and impacts dissemination to the CNS. We further showed titan cell formation alters the host response by reducing phagocytosis and stimulating a detrimental Th2-mediated response. The interaction between pathogens and their human hosts can be very complex, and the outcome depends on both host and pathogen responses. The host must sense pathogen associated molecular patterns (PAMPs), and then produce an appropriate immune response to kill the pathogen. Conversely, the pathogen must sense and respond to the host environment to promote its own survival. This proposal aims to identify critical alterations involved in the genesis of titan cells and their progeny, as well as define how their unique cellular structure impacts the host immune response and thereby, pathogenesis. Titan cells have a number of unique characteristics, thus the focus of our proposed investigations are to determine how these traits influence: 1) pathogen adaptation/survival in the host, and 2) alteration of PAMPs recognized by the host immune response. Our previous studies showed titan cells undergo ploidy changes associated with their formation and replication, and lead us to hypothesize these changes are critical for adaptation and survival in the host environment. Therefore, our first aim is to define cell cycle regulation needed to generate titan cells and their progeny. In our second aim, we will test the hypothesis that alternations in the titan cell wall impact PAMP recognition by the host, with the third aim determining how this altered sensing generates the detrimental immune response observed in response to titan cells. These studies will ultimately coalesce into multi-faceted antimicrobial therapies that combine targeting patho- gen-specific processes to limit pathogen adaptation and modulation of the host immune response to maximize beneficial host responses to reduce disease.