Host and fungal factors important for the cryptococcal intracellular niche

对隐球菌细胞内生态位很重要的宿主和真菌因素

• 批准号: 10717537
• 负责人: Felipe H Santiago-Tirado
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717537
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Area; Basic Science; Behavior; Biochemical; Biological; Biology; Buffers; Cause of Death; Cells; Cellular biology; Cessation of life; Characteristics; Clinical Research; Cryptococcus; Cryptococcus neoformans; Data; Development; Disease; Disease Progression; Early Endosome; Foundations; Fungal Genes; Generations; Genetic; Genetic Techniques; Geographic Locations; Glucuronic Acids; Goals; Hyaluronic Acid; Hybrids; Image; Immune; Immune Evasion; Immune signaling; Immune system; Immunocompromised Host; Immunologic Techniques; Immunologics; Incidence; Infection; Inflammatory; Inhalation; Intervention; Investigation; Knowledge; Link; Lysosomes; Macrophage; Mammalian Genetics; Mediating; Medical; Membrane; Microscopy; Mission; Modeling; Molecular; Mycoses; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Outcome; Pathogenesis; Patients; Permeability; Phagosomes; Phenotype; Phosphatidylinositols; Population; Prevention; Process; Property; Public Health; Reporting; Research; Resolution; Role; Signal Transduction; Surface; Techniques; Testing; Therapeutic Intervention; United States National Institutes of Health; Work; Yeasts; capsule; effective therapy; fungal genetics; fungus; immunological status; mortality; mutant; pathogen; pathogenic fungus; pathogenic microbe; permissiveness; prevent; rab GTP-Binding Proteins; therapeutically effective; Acquired Immunodeficiency Syndrome; Affect; Area; Basic Science; Behavior; Biochemical; Biological; Biology; Buffers; Cause of Death; Cells; Cellular biology; Cessation of life; Characteristics; Clinical Research; Cryptococcus; Cryptococcus neoformans; Data; Development; Disease; Disease Progression; Early Endosome; Foundations; Fungal Genes; Generations; Genetic; Genetic Techniques; Geographic Locations; Glucuronic Acids; Goals; Hyaluronic Acid; Hybrids; Image; Immune; Immune Evasion; Immune signaling; Immune system; Immunocompromised Host; Immunologic Techniques; Immunologics; Incidence; Infection; Inflammatory; Inhalation; Intervention; Investigation; Knowledge; Link; Lysosomes; Macrophage; Mammalian Genetics; Mediating; Medical; Membrane; Microscopy; Mission; Modeling; Molecular; Mycoses; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Outcome; Pathogenesis; Patients; Permeability; Phagosomes; Phenotype; Phosphatidylinositols; Population; Prevention; Process; Property; Public Health; Reporting; Research; Resolution; Role; Signal Transduction; Surface; Techniques; Testing; Therapeutic Intervention; United States National Institutes of Health; Work; Yeasts; capsule; effective therapy; fungal genetics; fungus; immunological status; mortality; mutant; pathogen; pathogenic fungus; pathogenic microbe; permissiveness; prevent; rab GTP-Binding Proteins; therapeutically effective

PROJECT SUMMARY / ABSTRACT Understanding how intracellular pathogens survive in their host cells has led to better management/pre- vention of their diseases, as well as discovery of fundamental biology. In this application, we aim to start elucidating the strategies and mechanisms used by one of the commonest fungal pathogens, Cryptococcus neoformans, to survive inside macrophages. The treatment of cryptococcal disease is subpar, resulting in mor- talities that range from 20% to almost 90%, depending on the geographical region. The ability of this fungus to survive inside host cells is one of the main drivers of disease progression, and clinical studies show that intra- cellular survival in macrophages correlates with patient’s mortality. However, the molecular mechanisms that govern internalization and the ability to survive intracellularly are not known, hampering the development of more effective therapeutics. Our long-term goal is to understand the cellular and molecular mechanisms behind intra- cellular survival, a significant gap in knowledge in the field. Moving towards that goal, the objectives of this application are to define and characterize the cryptococcal-containing phagosome (CCP) in macrophages, and understand the role of host and fungal factors in the generation of this intracellular niche. We hypothesize that Cryptococcus actively targets Rab GTPases and phosphoinositides to delay the normal maturation of its phag- osome. This allows fungal factors, such as capsular hyaluronic acid and glucuronic acid, to modulate acidification of the CCP, resulting in a fungal permissive niche. Pro-inflammatory signals, mediated in part by Rab20 effects on phagosomal maturation, counter this fungal manipulation and prevent niche establishment. We plan to test this hypothesis by (1) defining and characterizing the intracellular niche of C. neoformans in naïve and activated macrophages; and (2) identify and explore the role of fungal factors in niche establishment. If completed, we will have identified the genetic (fungal genes), phenotypic (CCP properties) and immunological (host’s immune sta- tus) characteristics that enable Cryptococcus to live intracellularly, allowing us to pinpoint potential areas of intervention to block intracellular replication. Completion of these aims will have a positive impact in the field by generating a detailed molecular description of the strategies Cryptococcus uses to survive in macrophages and how host cells respond. Moreover, given the scarcity of well characterized intracellular survival strategies in fungi, the knowledge created here will impact the understanding and studies of other pathogenic fungi as well.

项目摘要 /摘要 了解细胞内病原体如何在其宿主细胞中存活已导致更好的管理/预先治疗 其疾病的规定以及对基本生物学的发现。在此应用程序中，我们的目标是开始 阐明最常见的真菌病原体之一使用的策略和机制 Neoformans，在巨噬细胞内生存。隐球菌疾病的治疗不足，导致 取决于地理区域的世界，从20％到几乎90％不等。这种真菌的能力 在宿主细胞内生存是疾病进展的主要驱动因素之一，临床研究表明 - 巨噬细胞中的细胞存活与患者的死亡率相关。但是，分子机制 尚不清楚管理内在化和细胞内生存的能力，从而阻碍了更多的发展 有效的疗法。我们的长期目标是了解内部背后的细胞和分子机制 细胞存活，这是该领域知识的显着差距。朝着这个目标迈出的目标 应用是在巨噬细胞中定义和表征含隐球菌的吞噬体（CCP），并且 了解宿主和真菌因子在这种细胞内生态位的产生中的作用。我们假设这一点 加密赛积极靶向RAB GTPase和磷酸肌醇，以延迟其吞噬的正常成熟 osome。这允许真菌因子，例如囊囊添合酸和麸质酸，可以调节酸化。 CCP，导致真菌允许的利基市场。促炎信号，部分由Rab20效应介导 关于吞噬体成熟，对抗这种真菌操纵并防止利基建立。我们计划测试 通过（1）定义和表征新念珠菌的细胞内小裂，在幼稚和激活 巨噬细胞； （2）识别并探索真菌因素在利基建立中的作用。如果完成，我们将 已经确定了遗传（真菌基因），表型（CCP特性）和免疫学（宿主的免疫抑制 tus）特征，使得加密赛能够在细胞内生活，从而使我们能够指出 干预以阻止细胞内复制。这些目标的完成将对该领域产生积极影响 生成详细的分子描述，以在巨噬细胞和 宿主细胞如何响应。此外，鉴于特征良好的细胞内生存策略的稀缺 真菌，这里创建的知识也会影响对其他致病真菌的理解和研究。