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.

该R01应用探讨了新颖的作用胞质RNA传感模式识别受体MDA5播放 在介导对人类真菌病原体曲霉的抗药性中。我们对 免疫系统如何在免疫能力的个体中保持真菌感染的方式仍然不明显。 当前，了解真菌分生孢子与 真菌清除和宿主耐药性所需的组织居民吞噬细胞。我们的数据 表现出真菌分生孢子在触发胞质RNA传感MDA5受体中的新作用 IL28/IFNλ和CXCL10-CXCR3炎症性级联反应是响应宿主电阻所必需的 烟曲霉横跨各种真菌分离株。那是我们的中心假设是主持人 靶向A. fumigatus colidia的电阻途径是炎症的中心枢纽 防护性免疫对最广泛的烟曲霉分离株。在SA1中，我们检查了真菌 分生孢子生长动力学和对吞噬细胞介导的杀伤的抗性，可以触发MDA5/MAV 接收者。重要的是，我们还研究了烟曲霉分生孢子如何触发这一点的分子机制 胞质模式识别受体途径。在SA2中，我们确定需要的特定白细胞子集 烟曲霉挑战后的IL28/IFNλ表达和宿主电阻的MAV。这将使用 新型MAVS有条件的敲除小鼠线，专门检查了MDA5/MAV信号在 CCR2+单核细胞和中性粒细胞之间的细胞串扰，这对于维持至关重要 宿主抵抗烟曲霉。最后，在SA3中，我们阐明了CXCL10-CXCR3炎症的作用 介导嗜中性粒细胞对烟曲霉的抗宿主的抗性中的轴。总体而言，这项研究充满了关键 知识差距关于通过 新型MDA5/MAVS和CXCL10-CXCR3炎症级联反应的激活。这些数据以及 其他已发表的真菌免疫介导的抗性途径，可用于根据基于 他们潜在的侵入性曲霉菌病的敏感性。这种个性化的医学方法可能是 用于预测应进行早期，积极的监测和治疗真菌感染的患者 为了为患者带来更好的临床结果。