Trained immunity and the regulation of anti-fungal defense

摘要： 虽然经常被忽视作为一个重大的健康问题，肺部感染的真菌病原体存在 一个日益受到关注的临床问题。烟曲霉（Af）和新型隐球菌（Cn）是两种 影响全球免疫抑制患者的临床重要真菌病原体。这两种感染都是 很难治疗并且死亡率很高。更好地了解免疫机制 宿主对真菌的防御有望为未来开发新的免疫 以改善患者的治疗效果。肺巨噬细胞是重要的， 保护宿主免受真菌和其他肺部病原体的侵害。尽管肺巨噬细胞的作用很明确， 作为对不同病原体免疫的关键启动者，我们对以前感染史的理解 形状随后巨噬细胞对肺部真菌感染的反应仍然不清楚。而且安 大量的文献显示，肺中的巨噬细胞群体更加异质 比最初欣赏的，可以接受先天训练;对不同的次要反应的增强反应 挑战现在还理解，存在于肺中的肺泡巨噬细胞可以起源于胚胎巨噬细胞。 前体细胞（组织来源的肺泡巨噬细胞-TD-AM）或来自血液单核细胞（单核细胞来源的肺泡巨噬细胞 巨噬细胞-Mo-AM）。TD-AM和Mo-AM是否同样能够进行先天训练， 目前不清楚。也不知道先天训练是否是对任何感染性刺激的保守反应， 由特定的途径调节。在初步研究中，我们发现，用免疫原性的 Cn（HK-fbp 1）即使在药物诱导的Af感染的情况下，也可以赋予针对Af感染的异源保护作用。 免疫抑制和T细胞非依赖性方式。初步数据显示，中性粒细胞 和STAT 1依赖性信号是抗真菌单核细胞的重要调节因子， 单核细胞衍生的细胞。根据我们的综合观察，本项目的中心假设是： CCR 2 +mo是抗真菌免疫的关键介质，可以通过HK-fbp 1指导训练的mo-AM， 中性粒细胞和干扰素（IFN）级联的协调作用。我们将讨论两个相关的问题， 独立目的：目的1：研究HK-fbp 1免疫对肺先天性细胞引发的影响， 训练，以促进抗真菌免疫;目的2：破译中性粒细胞在调节 抗真菌训练免疫力。

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.