Pathogenesis of Cryptococcus Spores

隐球菌孢子的发病机制

• 批准号: 8259796
• 负责人: CHRISTINA M HULL
• 金额: $ 36.37万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259796
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Africa South of the Sahara; Alveolar Macrophages; Animals; Antibodies; Antifungal Agents; Biochemical; Biological Assay; Biotinylation; Carbohydrates; Cells; Cessation of life; Colony-forming units; Cryptococcal Meningitis; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Defect; Disease; Disease Progression; Employee Strikes; Exhibits; Fungal Spores; Genes; Genetic; Germination; Goals; Human; Immune; Immune response; Immune system; Immunocompromised Host; In Vitro; Individual; Infection; Investigation; Kinetics; Lead; Life; Ligands; Mammalian Cell; Mean Survival Times; Mediating; Membrane Proteins; Meningitis; Mission; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; Mycoses; Nature; Organ; Pathogenesis; Patients; Phagocytosis; Positioning Attribute; Prevention; Process; Property; Public Health; Reagent; Reproduction spores; Resistance; Signal Transduction; Speed; Surface; Testing; Time; Tissues; Tuberculosis; United States National Institutes of Health; Virulence; Yeasts; clinically relevant; fungus; insight; killings; macrophage; mortality; mouse model; mutant; novel; outcome forecast; particle; pathogen; prevent; public health relevance; receptor; respiratory; response; tool; treatment strategy; uptake

DESCRIPTION (provided by applicant): Our goal is to define the molecular mechanisms that control interactions between Cryptococcus neoformans and the mammalian immune system in an effort to ultimately prevent and treat fungal disease. Fungi are emerging pathogens, and morbidity and mortality are most apparent among the immunocompromised, especially in individuals with HIV/AIDS. The meningitis-causing fungus C. neoformans is particularly aggressive among people with AIDS, estimated to cause over a million cases of disease and ~600,000 deaths world-wide annually. The bulk of this burden is in Sub-Saharan Africa where the number of deaths from cryptococcal meningitis now appears to surpass the number of deaths from tuberculosis. In this region 13-44% of HIV/AIDS-related deaths are due to cryptococcosis, and mean survival times are on the order of a few weeks after onset. Worldwide, treatment with antifungal agents results in ~80% survival, and individual prognoses are strongly influenced by the availability of antifungal drugs and the immune status of the host. Little is known about the processes by which cryptococcal infection occurs, and we recognize a substantial gap in understanding the intersection between fungal pathogens and the host immune response. Studies over the last two decades have begun to define the relationships between C. neoformans yeast and the host immune system, but none has evaluated spores, likely infectious particles in nature. We have recently purified spores to homogeneity in numbers sufficient for comprehensive biochemical, molecular, and virulence studies. Using this novel reagent we have discovered that spores can cause disease in a mouse model and that murine alveolar macrophages, the first line of defense against respiratory fungal pathogens, interact fundamentally differently with spores than with yeast. Our findings place us in a unique position to ask questions about the C. neoformans-mammalian cell interface that have not been possible previously. We will take advantage of this major advance to investigate the fundamental properties of spores and their interactions with alveolar macrophages. Our hypothesis is that alveolar macrophages interact with spores via specific mechanisms that are distinct from those that mediate interactions with yeast. We will test our hypothesis by addressing the following three Aims. 1) Identify the receptors and ligands that mediate interactions between C. neoformans spores and murine alveolar macrophages. 2) Elucidate mechanisms that govern the ability of spores to survive inside macrophages. 3) Investigate the properties of spore-mediated disease using a murine model of infection. Our studies will provide insights fundamental to understanding how C. neoformans is recognized by the innate immune response and how cryptococcal disease is either suppressed in healthy individuals or disseminated in the immunocompromised. Ultimately, our findings promise to inform more general processes by which fungi cause disease, facilitating the discovery of novel prevention and/or treatment strategies. PUBLIC HEALTH RELEVANCE: Fungi, including Cryptococcus, are emerging pathogens that cause life-threatening diseases in humans, particularly people who are immunocompromised. Investigating interactions between Cryptococcus spores and the human immune system promises to provide the information necessary to understand how fungal spores cause disease. This project is relevant to public health and the mission of the NIH because it has the potential to lead to new strategies for preventing and/or treating severe fungal infections among the most vulnerable patients, including those with HIV/AIDS.

描述（由申请人提供）：我们的目标是确定控制新型隐球菌和哺乳动物免疫系统之间相互作用的分子机制，以最终预防和治疗真菌疾病。真菌是新出现的病原体，发病率和死亡率在免疫功能低下者中最为明显，特别是在艾滋病毒/艾滋病患者中。引起脑膜炎的真菌C.新型人在患有艾滋病的人群中特别具有攻击性，估计每年在全世界范围内导致超过一百万例疾病和约600，000例死亡。这一负担的大部分是在撒哈拉以南非洲，那里的隐球菌脑膜炎死亡人数现在似乎超过了结核病死亡人数。在这一地区，13-44%的艾滋病毒/艾滋病相关死亡是由于隐球菌病，平均存活时间大约为发病后几周。在世界范围内，抗真菌药物治疗导致约80%的存活率，并且抗真菌药物的可用性和宿主的免疫状态强烈影响个体疾病。隐球菌感染发生的过程知之甚少，我们认识到在理解真菌病原体和宿主免疫反应之间的交叉方面存在很大的差距。 过去二十年的研究已经开始定义C.新型酵母和宿主免疫系统，但没有人评估孢子，可能是自然界中的传染性颗粒。我们最近纯化孢子的数量足够全面的生化，分子和毒力研究的同质性。使用这种新型试剂，我们发现孢子可以在小鼠模型中引起疾病，并且小鼠肺泡巨噬细胞（对抗呼吸道真菌病原体的第一道防线）与孢子的相互作用与酵母菌的相互作用根本不同。我们的发现使我们处于一个独特的位置来询问关于C。这是以前不可能实现的。我们将利用这一重大进展来研究孢子的基本性质及其与肺泡巨噬细胞的相互作用。我们的假设是，肺泡巨噬细胞通过特定的机制与孢子相互作用，这些机制与介导与酵母相互作用的机制不同。我们将通过以下三个目标来检验我们的假设。1)鉴定介导C.新生孢子和鼠肺泡巨噬细胞。2)阐明控制孢子在巨噬细胞内存活能力的机制。3)用鼠感染模型研究孢子介导疾病的特性。我们的研究将为理解C。新生隐球菌是通过先天性免疫反应以及隐球菌病如何在健康个体中被抑制或在免疫功能低下者中传播来识别的。最终，我们的研究结果有望为真菌引起疾病的更一般过程提供信息，促进发现新的预防和/或治疗策略。 公共卫生关系：真菌，包括隐球菌，是新兴的病原体，可导致危及人类生命的疾病，特别是免疫功能低下的人。研究隐球菌孢子和人类免疫系统之间的相互作用有望提供了解真菌孢子如何引起疾病所需的信息。该项目与公共卫生和NIH的使命相关，因为它有可能导致预防和/或治疗最脆弱患者（包括艾滋病毒/艾滋病患者）严重真菌感染的新策略。