Trained immunity and the regulation of anti-fungal defense

训练有素的免疫力和抗真菌防御的调节

• 批准号: 10557883
• 负责人: Amariliz Rivera
• 金额: $ 63.08万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557883
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Alveolar Macrophages; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cells; Cessation of life; Clinical; Critical Pathways; Cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; Data; Defect; Development; Drug resistance; Embryo; Epigenetic Process; Exhibits; Exposure to; Fungal Vaccines; Future; Gene Targeting; Genetic Transcription; Health; Host Defense Mechanism; IFNAR1 gene; Immune; Immunity; Immunization; Immunocompromised Host; Immunosuppression; In Vitro; Infection; Infection Control; Inflammation; Interferons; Intervention; Life; Literature; Lung; Lung infections; Macrophage; Mediator; Medical; Molds; Mus; Mycoses; Natural Immunity; Opportunistic Infections; Pathway interactions; Patient-Focused Outcomes; Patients; Phagocytes; Pharmaceutical Preparations; Population; Predisposition; Publishing; Recording of previous events; Regulation; Role; STAT1 gene; Shapes; Siblings; Signal Transduction; Source; Stimulus; Systems Biology; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Vaccines; cross immunity; cytokine; fungus; immunogenic; improved; in vivo; insight; loss of function; lung pathogen; monocyte; mortality; neutrophil; novel; pathogen; pathogenic fungus; response; vaccine candidate

Abstract: Although often overlooked as a significant health problem, pulmonary infections with fungal pathogens present a clinical problem of growing concern. Aspergillus fumigatus (Af) and Cryptococcus neoformans (Cn) are two clinically important fungal pathogens that affect immunosuppressed patients worldwide. Both infections are difficult to treat and are associated with high mortality rates. A better understanding of immune mechanisms of host defense against fungi hold the promise of providing the basis for the future development of novel, immune based interventions to improve patient outcomes. Pulmonary macrophages are critical, front-line mediators of host protection against fungi and other pulmonary pathogens. Despite the well-defined role of lung macrophages as crucial initiators of immunity to diverse sets of pathogens, our understanding of how previous infection history shapes subsequent macrophage responses to fungal infection in the lung remain poorly defined. Moreover, an emerging body of literature has now revealed that macrophage populations in the lung are more heterogeneous than originally appreciated and can undergo innate training; an enhanced response to diverse secondary challenges. It is now also 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). Whether TD-AM and Mo-AM are equally capable of undergoing innate training is currently unclear. It is also unknown whether innate training is a conserved response to any infectious stimuli or regulated by specific pathways. In preliminary studies, we uncovered that priming with an immunogenic strain of Cn (HK-fbp1) could confer heterologous protection against infection with Af even in the context of drug-induced immunosuppression and in a T cell-independent manner. Preliminary data gathered, suggest that neutrophils and STAT1-dependent signals are important regulators of antifungal monocytes and their differentiation into monocyte-derived cells. Based on our aggregate observations, the central hypothesis of this project is that: CCR2+mo are critical mediators of antifungal immunity and can be instructed by HK-fbp1 into trained mo-AM via the coordinated actions of neutrophils and an interferon (IFN) cascade. We will address two related but independent aims: Aim 1: Investigate the impact of HK-fbp1 immunization to pulmonary innate cell priming and training to promote antifungal immunity; Aim 2: Decipher the contributions of neutrophils in the regulation of antifungal trained immunity.

抽象的： 尽管经常被视为重大健康问题，但存在真菌病原体的肺部感染 一个日益关注的临床问题。曲霉菌（AF）和加密赛车（CN）为两个 影响全球免疫抑制患者的临床重要真菌病原体。两种感染都是 难以治疗，并且与高死亡率有关。更好地了解 对真菌的寄宿国防有望为新颖，免疫的未来发展提供基础 基于改善患者预后的干预措施。肺巨噬细胞是关键的，前线介体 宿主防止真菌和其他肺病原体。尽管肺巨噬细胞的角色定义明确 作为对多种病原体的免疫力的关键启动者，我们对先前感染历史的理解 形状随后对肺部真菌感染的巨噬细胞反应仍然很差。而且， 文学的新兴体系已经表明，肺中的巨噬细胞种群更异质 比最初的赞赏，可以接受先天培训；对多样的次要的反应增强 挑战。现在也可以理解，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（单核细胞衍生的牙槽 巨噬细胞-MO-AMS）。 TD-AM和MO-AM是否同样能够接受先天培训 目前不清楚。尚不清楚天生训练是对任何传染性刺激还是 由特定途径调节。在初步研究中，我们发现了以免疫原性的启动 CN（HK-FBP1）即使在药物引起 免疫抑制和T细胞无关的方式。收集的初步数据，表明中性粒细胞 与STAT1依赖性信号是抗真菌单核细胞的重要调节剂，它们的分化为 单核细胞衍生的细胞。根据我们的总体观察，该项目的核心假设是： CCR2+MO是抗真菌免疫的关键介质，可以通过HK-FBP1指示通过训练有素的Mo-Am通过 中性粒细胞和干扰素（IFN）级联的协调作用。我们将解决两个相关的问题，但是 独立目的：目标1：研究HK-FBP1免疫对肺部先天细胞启动和 培训以促进抗真菌免疫；目标2：破译中性粒细胞在调节中的贡献 抗真菌训练的免疫力。