Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity

肺泡巨噬细胞依赖性抗真菌先天免疫的新机制

• 批准号: 10536600
• 负责人: Terry W Wright
• 金额: $ 54万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-08 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536600
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adrenal Cortex Hormones; Alveolar Macrophages; Antibiotic Therapy; Antifungal Agents; Area; Basic Science; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cells; Characteristics; Chitinase; Chromosome Mapping; Data; Disease; Event; FVB Mouse; Failure; Genetic; Goals; Growth; Host Defense; Immunity; Immunocompetent; Immunocompromised Host; Impairment; In Vitro; Inbred Strains Mice; Inbreeding; Infection; Inflammatory; Ingestion; Injury; Interferon Type II; Knowledge; Laboratories; Life; Lung; Macrophage; Maps; Mediating; Mission; Modeling; Mouse Strains; Mus; Mycoses; Natural Immunity; Organism; Outcome; Patient Care; Pattern recognition receptor; Phagocytes; Phagocytosis; Phagosomes; Phenotype; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Predisposition; Production; Productivity; Proteins; Quantitative Trait Loci; Reagent; Receptor Protein-Tyrosine Kinases; Regulation; Research; Research Design; Resistance; Resistance to infection; Role; Sentinel; Surface; T-Lymphocyte; Testing; Therapeutic; Time; United States National Institutes of Health; Work; adaptive immunity; candidate identification; drug discovery; genomic locus; improved; in vivo; inhibitor; insight; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; pathogen; pathogenic fungus; programs; protein expression; rational design; receptor; resistance gene; respiratory; tool; translational study; transmission process; treatment strategy

Pneumocystis pneumonia (PcP) remains a serious life-threatening respiratory fungal infection of immunocompromised patients, and one of the most common AIDS-defining illnesses in the US and the world. PcP-related mortality rates have changed little over the past two decades, likely due to our inability to adequately treat the infection without exacerbating immunopathogenesis. Adjunctive corticosteroids are used to suppress inflammatory injury during antibiotic treatment, but the benefit of these broadly acting agents is uncertain. The mechanisms by which Pc is recognized and cleared from the lung remain incompletely understood. Alveolar macrophages (AMs) are at the frontline of the host-pathogen interaction, and serve as important effectors of pulmonary host defense against Pneumocystis. Macrophages possess an array of PRR that have the potential to recognize Pc, but they are typically ineffective for host defense when CD4+ T cell help is not available. The reason for this is unknown, but it has been suggested that Pc may actively avoid or suppress macrophage mediated host defense to insure survival and transmission. Our laboratory has identified an inbred mouse strain which is unique in its ability to resist Pc infection in the absence of T cells. The resistance phenotype requires the presence of AMs, and can be overridden by reprogramming the resistant AMs to a susceptible M1 biased phenotype. The identification of resistant and susceptible macrophage phenotypes will provide an opportunity to explore the divergent host-pathogen interactions associated with either protection or infection. The overarching hypothesis of this proposal is that differential macrophage polarization, phagocytic processing of Pc, and antifungal effector production dictates the outcome of the Pc-AM interaction. To test this hypothesis we will utilize the resistant and susceptible mouse models described in our Preliminary Studies. The identification of new therapeutic strategies for the treatment of fungal diseases is an active area of drug-discovery research. Our long-term goal is to understand the mechanisms regulating macrophage mediated innate immunity in the lung to facilitate the rational design of therapeutic strategies to enhance host defense while limiting immunopathogenesis. To accomplish this goal we propose Specific Aims that will: 1) define functional differences in the phagocytic machinery of resistant and susceptible AMs that dictate the outcome of infection; 2) explore novel antifungal functions for chitinase-like proteins (Chi3l3) and TAM receptors (MerTK); and 3) map the Pc resistance locus and identify resistance-associated effector molecules that contribute to protective antifungal innate immunity. Our Preliminary Studies demonstrate that AMs can be programmed for innate protection against this opportunistic fungal pathogen, and suggest that modifying macrophage function may represent a viable strategy to enhance antifungal host defense.

肺炎肺炎(PCP)是一种严重威胁生命的呼吸道真菌感染。 免疫功能低下的患者，是美国和美国最常见的定义艾滋病的疾病之一 世界。与五氯苯酚相关的死亡率在过去二十年中几乎没有变化，可能是因为我们无法 充分治疗感染，而不会加剧免疫病理。辅助性皮质类固醇用于 在抗生素治疗过程中抑制炎性损伤，但这些广泛作用的药物的好处是 不确定。Pc被识别和从肺中清除的机制仍然不完全 明白了。肺泡巨噬细胞(AM)处于宿主-病原体相互作用的最前线，并作为 肺宿主防御肺孢子虫的重要效应物。巨噬细胞具有一系列PRR 它们具有识别Pc的潜力，但当CD4+T细胞帮助时，它们通常对宿主防御无效 不可用。原因尚不清楚，但有人建议Pc可能会主动回避或压制 巨噬细胞介导宿主防御以确保生存和传播。我们实验室鉴定出一种近交系 在没有T细胞的情况下抵抗Pc感染的独特能力的小鼠品系。耐药表型 需要AM的存在，并可以通过将抗性AM重新编程为敏感的M1来覆盖 有偏见的表型。耐药和易感巨噬细胞表型的鉴定将提供一种 探索与保护或感染相关的不同宿主-病原体相互作用的机会。这个 这一建议的主要假设是，巨噬细胞的分化极化，Pc的吞噬处理， 而抗真菌效应剂的产生决定了Pc-AM相互作用的结果。为了检验这一假设，我们将 利用我们的初步研究中描述的抵抗和敏感的小鼠模型。身份的鉴定 治疗真菌疾病的新治疗策略是药物发现研究的活跃领域。我们的 长期目标是了解肺内巨噬细胞介导的先天免疫的调节机制。 促进合理设计治疗策略，在限制宿主防御的同时加强宿主防御 免疫致病机制。为了实现这一目标，我们提出了具体的目标：1)定义功能差异 在决定感染结果的耐药和敏感AM的吞噬机制中；2)探索 几丁质酶样蛋白(Chi313)和受体(MerTK)的新抗真菌功能；3)定位Pc 抗性基因定位和识别有助于保护性抗真菌的抗性相关效应分子 先天免疫力。我们的初步研究表明，AM可以被编程为先天保护 这种机会性的真菌病原体，并表明改变巨噬细胞的功能可能代表着一种可行的 加强抗真菌寄主防御的策略。