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.

摘要： 虽然经常被忽视是一个重大的健康问题，但肺部感染的真菌病原体仍然存在。 一个日益令人担忧的临床问题。烟曲霉(Af)和新生隐球菌(Cn)是两种 影响世界各地免疫抑制患者的临床重要真菌病原体。这两种感染都是 难以治疗，并与高死亡率有关。更好地了解脑炎的免疫机制 寄主对真菌的防御有望为未来新型、免疫 以改善患者预后为基础的干预措施。肺巨噬细胞是关键的、前线的介质 宿主对真菌和其他肺部病原体的保护。尽管肺巨噬细胞的作用是明确的 作为对多种病原体免疫的关键启动者，我们对以前的感染史的理解 肺部真菌感染后巨噬细胞反应的形态仍不明确。此外，一个 新出现的文献表明，肺中的巨噬细胞群更加异质性。 比最初意识到的更好，并可以接受先天训练；对不同的次要因素的增强反应 挑战。现在还了解到，肺中存在的肺泡巨噬细胞可以起源于胚胎。 前体(组织来源的肺泡巨噬细胞-TD-AM)或来自血液的单核细胞(单核细胞来源的肺泡 巨噬细胞-钼-AM)。TD-AM和MO-AM是否同样有能力进行先天训练 目前尚不清楚。也不知道先天训练是对任何感染性刺激的保守反应还是 由特定的途径调节。在初步研究中，我们发现用一种免疫原性菌株 CN(HK-FBP1)即使在药物诱导的情况下也能提供对Af感染的异种保护作用 免疫抑制和非T细胞依赖的方式。收集的初步数据表明，中性粒细胞 和STAT1依赖的信号是抗真菌单核细胞及其分化为 单核细胞来源的细胞。根据我们的综合观察，该项目的中心假设是： CCR2+mo是抗真菌免疫的关键介质，可由HK-FBP1通过 中性粒细胞和干扰素(干扰素)的协同作用。我们将讨论两个相关的但 独立目标：目标1：研究HK-FBP1免疫对肺固有细胞启动和免疫的影响 训练以促进抗真菌免疫；目标2：破译中性粒细胞在调节 抗真菌训练的免疫力。