Fungal spore sensing by MDA5 is necessary for antifungal immunity against Aspergillus fumigatus

MDA5 的真菌孢子感应对于烟曲霉的抗真菌免疫是必要的

• 批准号: 10222512
• 负责人: JOSHUA J OBAR
• 金额: $ 52.83万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222512
• 关键词: Acquired Immunodeficiency Syndrome; Allogenic; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Automobile Driving; Biological; CXCL10 gene; CXCR3 gene; Clinical; Data; Development; Disease; Event; Fungal Spores; Genetic Polymorphism; Goals; Growth; Host resistance; Human; Immune; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Knowledge; Leukocytes; Mediating; Molecular; Monitor; Morbidity - disease rate; Mucosal Immunity; Mycoses; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern recognition receptor; Phagocytes; Play; Predisposition; Publishing; RNA; Reproduction spores; Research; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Stem cell transplant; Testing; Tissues; base; conditional knockout; fungus; immunomodulatory strategy; improved outcome; insight; monocyte; mortality; neutrophil; novel; pathogenic fungus; pathogenic virus; patient population; patient stratification; personalized medicine; receptor; recruit; response; risk stratification

This R01 application explores the novel role the cytosolic RNA-sensing pattern-recognition receptor MDA5 plays in mediating host resistance against the human fungal pathogen Aspergillus fumigatus. Our understanding of how the immune system keeps fungal infections at bay in immune competent individuals remains ill-defined. Currently, there is a critical gap in understanding the early interactions between fungal conidia and tissue-resident phagocytes that are necessary for fungal clearance and host resistance. Our data demonstrate a novel role of fungal conidia in triggering the cytosolic RNA-sensing MDA5 receptor and initiating an IL28/IFNλ and CXCL10-CXCR3 inflammatory cascade which is necessary for host resistance in response to Aspergillus fumigatus across a wide array of fungal isolates. Thus, our central hypothesis is that host resistance pathways targeting A. fumigatus conidia serve as central hubs of inflammation providing protective immunity against the broadest range of A. fumigatus isolates. In SA1 we examine how fungal conidia growth dynamics and resistance to phagocyte-mediated killing enables triggering of the MDA5/MAVS receptor. Importantly, we also examine the molecular mechanism(s) of how A. fumigatus conidia trigger this cytosolic pattern-recognition receptor pathway. In SA2 we identify the specific leukocyte subsets which require MAVS for IL28/IFNλ expression and host resistance following A. fumigatus challenge. This will be done using novel Mavs conditional knock-out mouse lines, specifically examining the role of MDA5/MAVS signaling in the cellular cross-talk between CCR2+ monocyte and neutrophil, which has been shown to be critical for maintaining host resistance against A. fumigatus. Finally, in SA3 we elucidate the role of the CXCL10-CXCR3 inflammatory axis in mediating neutrophil-dependent host resistance against A. fumigatus. Overall, this research fills a critical knowledge gap regarding the mechanisms of protective mucosal immunity against A. fumigatus conidia through the activation of a novel MDA5/MAVS and CXCL10-CXCR3 inflammatory cascade. These data, together with other published fungal immune-mediated resistance pathways, could be used to risk stratify patients based on their potential susceptibility to developing invasive aspergillosis. This personalized medicine approach could be used to predict patients that should undergo early, aggressive monitoring and treatment for fungal infections in order to drive better clinical outcomes for patients.

这个R 01应用探索了胞质RNA传感模式识别受体MDA 5所起的新作用 介导宿主对人类真菌病原体烟曲霉的抗性。我们理解 免疫系统如何阻止真菌感染进入免疫活性个体仍然不清楚。 目前，在理解真菌分生孢子和真菌孢子之间的早期相互作用方面存在着严重的差距。 真菌清除和宿主抗性所必需的组织驻留吞噬细胞。我们的数据 证明了真菌分生孢子在触发胞质RNA敏感MDA 5受体和启动 IL 28/IFNλ和CXCL 10-CXCR 3炎性级联反应，其是响应以下的宿主抗性所必需的： 烟曲霉在一系列真菌分离株中的分布。因此，我们的中心假设是， 针对A.烟曲霉分生孢子作为炎症的中心枢纽， 对最广泛的A.烟曲霉菌株在SA 1中，我们研究了真菌 分生孢子生长动力学和对吞噬细胞介导的杀伤的抗性使得能够触发MDA 5/MAVS 受体的重要的是，我们还研究了A.烟曲霉分生孢子触发这一点 胞质模式识别受体途径。在SA 2中，我们确定了特定的白细胞亚群， 用MAVS法检测A.烟曲霉菌攻毒。这将使用 新的Mavs条件性敲除小鼠系，特别是研究了MDA 5/MAVS信号传导在Mavs条件性敲除小鼠中的作用。 CCR 2+单核细胞和中性粒细胞之间的细胞串扰，已被证明是维持细胞增殖的关键。 宿主对A.烟熏。最后，在SA 3中，我们阐明了CXCL 10-CXCR 3炎性细胞因子的作用。 轴介导嗜热菌依赖的宿主对A.烟熏。总的来说，这项研究填补了一个关键的 关于抗A.烟曲霉孢子穿透 一种新的MDA 5/MAVS和CXCL 10-CXCR 3炎症级联反应的激活。这些数据，连同 其他已发表的真菌免疫介导的耐药途径，可用于基于以下因素对患者进行风险分层： 他们对侵袭性曲霉病的潜在易感性。这种个性化的医疗方法可能是 用于预测应接受早期，积极监测和治疗真菌感染的患者， 为患者带来更好的临床效果。