The role of pathogen-experienced macrophage subsets in mediating lung immunity and heterologous protection

经历病原体的巨噬细胞亚群在介导肺免疫和异源保护中的作用

• 批准号: 10753773
• 负责人: William Clark Gause
• 金额: $ 77.95万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753773
• 关键词: 2019-nCoV; Address; Affect; Alveolar Macrophages; Antifungal Agents; Antigens; Basic Science; Biology; COVID-19; COVID-19 pandemic; Cells; Cessation of life; Communicable Diseases; Data; Defect; Embryo; Epigenetic Process; Event; Experimental Models; Exposure to; Gene Targeting; Goals; Health; Helminths; IFNAR1 gene; Immune; Immune response; Immunity; Impairment; In Vitro; Individual; Infection; Inflammation; Interferons; Knowledge; Literature; Lower Respiratory Tract Infection; Lung; Lung infections; Macrophage; Maintenance; Maps; Mediating; Mediator; Memory; Modification; Molecular; Morbidity - disease rate; Mus; Mycoses; Natural Immunity; Nature; Ontology; Outcome; Parasites; Pathway interactions; Play; Population; Primary Infection; Publishing; Recording of previous events; Role; STAT1 gene; Shapes; Signal Transduction; Specificity; Standardization; Stimulus; Testing; Therapeutic; Tissue Preservation; Tissues; Training; Viral; Virus; Virus Diseases; antimicrobial; blastomere structure; chronic infection; embryo cell; experience; extracellular; fungus; gain of function; helminth infection; human disease; in vivo; innate immune function; insight; instructor; loss of function; lung pathogen; monocyte; mortality; mouse model; neutrophil; novel; pathogen; pathogenic fungus; pathogenic virus; programs; pulmonary function; recruit; response; tissue injury; transcriptome

ABSTRACT: Infections of the lung significantly impact health worldwide, with non-tuberculosis lower respiratory infections causing 2.7 million deaths annually and chronic infections significantly contributing to impaired lung function and morbidity. Pulmonary macrophages are critical, front-line mediators of host protection against helminth parasites, fungi, and viruses. Despite the well-defined role of lung macrophages as crucial initiators of immunity to diverse sets of pathogens, our understanding of the cellular and molecular events that regulate macrophage responses in the lung remain poorly defined. For example, the precise mechanisms that allow pulmonary macrophages to eliminate both intracellular and extracellular pathogens while simultaneously mitigating tissue injury and preserving lung function remain elusive. Further, an emerging body of literature has now revealed that macrophage populations in the lung are more heterogeneous than originally appreciated. Specifically, it is now understood that alveolar macrophages present in the lung can originate from embryonic precursors (tissue- derived alveolar macrophages-TD-AMs) or from blood monocytes (monocyte-derived alveolar macrophages- Mo-AMs). Despite this important advance, it is currently unclear whether these ontologically distinct pulmonary macrophage populations perform comparable or distinct functions in mediating protection (reduction in pathogen burdens and/or maintenance of tissue integrity). Also, whether these distinct macrophage populations initiate similar or unique effector functions in the context of helminth, fungal, or viral challenges remains unknown. Finally, our understanding of how a previous exposure to one pulmonary pathogen alters the responsiveness of lung macrophages to a subsequent challenge with a distinct pathogen is poorly understood. This important gap in knowledge has become extremely evident during the COVID-19 pandemic where individual outcomes vary dramatically and we have a poor understanding of how one’s infectious past may contribute to these differences. The leaders of this project will employ their combined expertise to address these critical questions. The central hypothesis of this application is that infection with diverse pathogens program TD-AMs and Mo-AMs to perform distinct functions against heterologous pathogens while mitigating tissue injury. We further hypothesize that the pathogen-induced response of TD-AMs and Mo-AMs is critically shaped by neutrophil-derived signals and type I and III interferons. In three distinct and complementary aims we will use a combination of discovery-based studies combined with targeted in vitro and in vivo approaches to define the overlapping and unique contributions of tissue-derived macrophages and recruited monocyte-derived cells to host protective responses following helminth, fungal or viral infections. This thorough and comprehensive approach will allow us to gain an unprecedented understanding of fundamental innate immune functions. This novel insight may inform therapeutic strategies to target lung macrophage populations in a manner that will allow for the fine tuning of inflammation and pulmonary infection outcomes.

抽象的： 肺部感染严重影响全世界的健康，其中包括非结核性下呼吸道感染 每年有 270 万人死亡，慢性感染严重导致肺功能受损和 肺巨噬细胞是宿主抵御蠕虫寄生虫的重要前线介质， 尽管肺巨噬细胞作为多种免疫的关键启动子的作用已明确。 病原体组，我们对调节巨噬细胞反应的细胞和分子事件的理解 例如，肺部巨噬细胞的精确机制仍不清楚。 消除细胞内和细胞外病原体，同时减轻组织损伤 此外，现在有大量文献表明，保护肺功能仍然是一个难题。 具体来说，肺部的巨噬细胞群比最初认识的更加异质。 据了解，肺中存在的肺泡巨噬细胞可以起源于胚胎前体（组织- 衍生的肺泡巨噬细胞-TD-AM）或来自血液单核细胞（单核细胞衍生的肺泡巨噬细胞- 尽管取得了这一重要进展，但目前尚不清楚这些本体论上不同的肺是否 巨噬细胞群在介导保护（减少病原体）方面发挥相似或不同的功能 负担和/或维持组织完整性）此外，这些不同的巨噬细胞群是否启动。 在蠕虫、真菌或病毒挑战中相似或独特的效应器功能仍然未知。 最后，我们对先前接触一种肺部病原体如何改变其反应性的理解 人们对肺巨噬细胞随后受到不同病原体攻击的这一重要差距知之甚少。 在 COVID-19 大流行期间，知识的变化变得极其明显，个人结果各不相同 戏剧性地，我们对一个人的传染性过去可能如何导致这些差异了解甚少。 该项目的领导者将利用他们的综合专业知识来解决这些关键问题。 该应用的假设是，不同病原体的感染程序 TD-AM 和 Mo-AM 执行 对异源病原体具有独特的功能，同时减轻组织损伤。 TD-AM 和 Mo-AM 的病原体诱导反应主要由中性粒细胞衍生的信号和类型决定 I 和 III 干扰素在三个不同且互补的目标中，我们将结合使用基于发现的干扰素。 研究与有针对性的体外和体内方法相结合，以确定重叠和独特的贡献 组织来源的巨噬细胞并招募单核细胞来源的细胞来宿主保护反应 这种彻底而全面的方法将使我们能够预防寄生虫、真菌或病毒感染。 对基本先天免疫功能的前所未有的理解可能会提供信息。 以肺巨噬细胞群为目标的治疗策略，以允许微调 炎症和肺部感染的结果。