Inflammatory Caspases in Innate Immunity and Inflammation

 描述(申请人提供)：烟曲霉(A.fumigatus)是一种重要的人类真菌病原体，在免疫功能低下的患者中导致显著的发病率和死亡率。近年来，我们对模式识别受体(PRRs)调节病原体感知的分子机制的研究取得了重要进展，包括Toll样受体(TLRs)、Nod样受体(NLRs)、AIM2样受体(ALR)和RIG-I样受体(RLRs)。NLR和ALR家族的某些成员组装了一个细胞质的多蛋白复合体，称为“炎症体”，它激活caspase-1，并诱导促炎症细胞因子IL-1β和IL-18的成熟和分泌。我们最近的研究表明，烟曲霉的胞内感应需要NLRP3和AIM2之间的协调作用 炎症性小体。然而，导致这些保护性反应激活的分子机制和信号通路是完全未知的。在这项拨款续期申请中，我们建议研究调节烟曲霉菌感染驱动的炎症体激活的信号通路。这项提议的完成有望识别直接感知烟曲霉菌的主要先天免疫感受器，并揭开调节炎症小体形成对烟曲霉菌反应的分子机制。这些发现有望确定可作为治疗干预目标的新信号通路。

 DESCRIPTION (provided by applicant): Aspergillus fumigatus (A. fumigatus) is an important human fungal pathogen, which is responsible for significant morbidity and mortality amongst immunocompromised patients. In recent years, we have made important progress in understanding the molecular mechanisms that regulate sensing of pathogens by pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), AIM2-like receptors (ALRs) and RIG-I like receptors (RLRs). Certain members of the NLR and ALR family assemble a cytoplasmic multi-protein complex termed the 'inflammasome', which activates caspase-1 and induces maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Our recent study demonstrated that intracellular sensing of A. fumigatus requires a coordinated effort between the NLRP3 and AIM2 inflammasomes. However, the molecular mechanisms and signaling pathways leading to activation of these protective responses are completely unknown. In this grant application for renewal, we propose to investigate the signaling pathways regulating activation of inflammasomes driven by A. fumigatus infection. Completion of this proposal is expected to identify the major innate immune sensors that are directly sensing A. fumigatus and unravel the molecular mechanisms that regulate formation of inflammasomes in response to A. fumigatus. These discoveries are expected to identify novel signaling pathways that could be targeted by therapeutic interventions.