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: 9897466
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897466
• 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; Organ Transplantation; Organism; Outcome; Partner in relationship; Pathogenesis; Pathway interactions; Pattern; Pattern Recognition; Phagocytosis; Pharmacotherapy; Ploidies; Polyploid Cells; Process; Production; Resistance; Signal Pathway; Stress; System; Tern; Testing; Th2 Cells; Thick; Titan; Transplant Recipients; Virulence; Yeasts; antimicrobial; capsule; cell type; crosslink; human disease; immune function; improved; in vivo; macrophage; mortality; novel; 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 patho- gen-specific processes to limit pathogen adaptation and modulation of the host immune response to maximize beneficial host responses to reduce disease.

项目摘要 据估计，侵袭性真菌感染每年导致150万人死亡，其中隐球菌感染是一种常见的真菌感染。 新生儿（Cn）感染导致几乎一半的死亡，由于真菌感染。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 表明目前的抗真菌药物治疗对免疫功能低下的个体是不够的。这一悖论 表明我们缺少了Cn-宿主相互作用的关键成分。隐球菌细胞的特征 在感染过程中发现，Cn产生一种独特的细胞类型-称为“泰坦细胞”-在感染过程中 改变宿主和病原体之间的相互作用这些巨噬细胞是在宿主肺部 环境中，并且比典型尺寸的Cn细胞大5- 10倍。 我们以前证明，泰坦细胞的生产是至关重要的毒力和影响传播到 CNS。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宿主的免疫反应来改变宿主的免疫反应。 一种有害的Th 2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 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 相关的分子模式（PAMP），然后产生适当的免疫反应来杀死 病原体相反，病原体必须感知并响应宿主环境，以促进其自身 生存该提案旨在确定参与泰坦细胞发生的关键性改变， 后代，以及定义其独特的细胞结构如何影响宿主免疫应答，从而， 发病机制 泰坦电池具有许多独特的特征，因此我们建议的研究重点是 确定这些特征如何影响：1）病原体在宿主中的适应/存活，以及2）PAMP的改变 由宿主免疫反应识别。我们以前的研究表明泰坦细胞会发生倍性变化 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必需的。在我们的第二个目标中，我们将检验以下假设： 泰坦细胞壁中的变化影响宿主对PAMP的识别，第三个目的是确定这种变化如何影响宿主对PAMP的识别。 改变的感应产生在对泰坦细胞的应答中观察到的有害免疫应答。 这些研究最终将结合成多方面的抗菌治疗，联合收割机靶向病理， 限制病原体适应和调节宿主免疫应答的基因特异性过程， 有益的宿主反应以减少疾病。