Impact of Cryptococcus Titan Cells on Pathogenesis.

隐球菌泰坦细胞对发病机制的影响。

• 批准号: 10371091
• 负责人: Kirsten Nielsen
• 金额: $ 50.2万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-25 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371091
• 关键词: AIDS/HIV problem; Adrenal Cortex Hormones; Affect; Antifungal Agents; Brain; Caliber; Cancer Patient; Cell Cycle Regulation; Cell Size; Cell Survival; Cell Wall; Cell Wall Alteration; Cells; Cellular Structures; Cessation of life; Characteristics; Clinical; Complex; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Disease; Disease Outcome; Dwarfism; Environment; Failure; Foundations; Genetic; Genomics; Heritability; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Infection; Inhalation; Investigation; Lead; Life; Lung; Lung infections; Mediating; Meningitis; Modification; Molecular; Morphology; Mutation; Mycoses; Natural Immunity; Nature; Neuraxis; Organism; Outcome; Pathogenesis; Pathway interactions; Pattern; Pattern Recognition; Persons; Phagocytosis; Pharmacotherapy; Ploidies; Polyploid Cells; Process; Production; Resistance; Signal Pathway; Stress; Testing; Th2 Cells; Thick; Titan; Virulence; Yeasts; antimicrobial; capsule; cell type; crosslink; human disease; immune function; improved; in vivo; macrophage; mortality; novel; organ transplant recipient; pathogen; patient population; prevent; response; trait

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 pathogen-specific processes to limit pathogen adaptation and modulation of the host immune response to maximize beneficial host responses to reduce disease.

项目概要 据估计，隐球菌等侵袭性真菌感染每年会导致一百五十万人死亡 新型隐球菌 (Cn) 感染导致几乎一半的真菌感染死亡。 Cn在健康人中很少见 个人，表明免疫系统能够预防疾病。但临床上观察到的死亡率却很高 表明当前的抗真菌药物治疗对于免疫功能低下的个体来说是不够的。这个悖论 表明我们缺少 Cn-宿主相互作用的关键组成部分。隐球菌细胞的表征 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” 改变宿主与病原体的相互作用。这些泰坦细胞是响应宿主肺部而产生的 环境，比典型尺寸的 Cn 电池大 5-10 倍。 我们之前证明了泰坦细胞的产生对于毒力和影响传播至 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作用和刺激来改变宿主反应 有害的 Th2 介导的反应。病原体与其人类宿主之间的相互作用可能非常严重 复杂，结果取决于宿主和病原体的反应。宿主必须感知病原体 相关的分子模式（PAMP），然后产生适当的免疫反应来杀死 病原。相反，病原体必须感知宿主环境并对其做出反应，以促进其自身的发展。 生存。该提案旨在确定泰坦细胞及其起源中涉及的关键改变 后代，以及定义它们独特的细胞结构如何影响宿主免疫反应，从而， 发病。 泰坦细胞具有许多独特的特征，因此我们提出的研究重点是 确定这些性状如何影响：1) 宿主中病原体的适应/生存，以及 2) PAMP 的改变 被宿主免疫反应识别。我们之前的研究表明泰坦细胞经历倍性变化 与它们的形成和复制有关，并使我们假设这些变化对于 在宿主环境中的适应和生存。因此，我们的首要目标是定义细胞周期调控 产生泰坦细胞及其后代所需的。在我们的第二个目标中，我们将检验以下假设： 泰坦细胞壁的变化影响宿主对 PAMP 的识别，第三个目标是确定这种变化如何 传感的改变会产生对泰坦细胞的有害免疫反应。 这些研究最终将融合成多方面的抗菌疗法，结合针对病原体特异性过程来限制病原体适应和调节宿主免疫反应，以最大限度地发挥作用。 有益的宿主反应以减少疾病。