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: 10311998
• 负责人: Terry W Wright
• 金额: $ 54.39万
• 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/10311998
• 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; Maps; Masks; 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; 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; base; drug discovery; genomic locus; improved; in vivo; inhibitor; insight; macrophage; 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.

肺炎肺炎肺炎（PCP）仍然是严重威胁生命的呼吸真菌感染 免疫功能低下的患者，以及美国最常见的艾滋病疾病之一 世界。在过去的二十年中，与PCP相关的死亡率几乎没有变化，这可能是由于我们无法 充分治疗感染，而不会加剧免疫发作。辅助性皮质类固醇用于 抑制抗生素治疗期间的炎症性损伤，但这些广泛作用剂的好处是 不确定。从肺中识别和清除PC的机制不完全 理解。肺泡巨噬细胞（AMS）位于宿主病原体相互作用的前线，并用作 肺宿主防御肺炎藻的重要效应因子。巨噬细胞拥有一系列PRR 有可能识别PC的潜力，但是当CD4+ T细胞帮助时，它们通常对宿主防御无效 不可用。原因是未知的，但有人建议PC可以主动避免或抑制 巨噬细胞介导的宿主防御以确保生存和传播。我们的实验室已经确定了一个近亲 小鼠应变在没有T细胞的情况下抵抗PC感染的能力是独特的。电阻表型 需要AM的存在，可以通过将抗性AM重编程为易感M1来覆盖 偏见的表型。抗性和易感巨噬细胞表型的鉴定将提供 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 该提议的总体假设是差异巨噬细胞极化，PC的吞噬处理， 抗真菌效应子的产生决定了PC-AM相互作用的结果。为了检验这个假设，我们将 利用我们的初步研究中描述的抗性和易感小鼠模型。识别 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 长期目标是了解调节巨噬细胞介导的先天免疫的机制 促进治疗策略的合理设计，以增强宿主防御 免疫致病发生。为了实现这一目标，我们提出的特定目标将：1）定义功能差异 在决定感染结果的抗性和易感性AM的吞噬机制中； 2）探索 几丁质酶样蛋白（CHI3L3）和TAM受体（MERTK）的新型抗真菌功能； 3）映射PC 抗性基因座并鉴定与抗性相关的效应分子，这些分子有助于保护性抗真菌 先天免疫。我们的初步研究表明，可以对AMS进行编程，以防止 这种机会性真菌病原体，并表明修饰巨噬细胞功能可能代表可行的 增强抗真菌宿主防御的策略。