Implicating a previously unknown Dectin1-RIPK2-CARD9 signaling in providing resistance against Leishmania major infection

暗示以前未知的 Dectin1-RIPK2-CARD9 信号传导对利什曼原虫重大感染的抵抗力

• 批准号: 10570868
• 负责人: Prajwal Gurung
• 金额: $ 50.48万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-24 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570868
• 关键词: Adaptor Signaling Protein; Affect; Antifungal Agents; Area; BCL10 gene; Bacterial Infections; Basic Science; Biochemical; Biology; Cell Death; Cells; Clinical; Communicable Diseases; Complex; Cutaneous Leishmaniasis; Cytoplasm; Data; Development; Disease; Etiology; Event; Family; Genetic; Goals; Grant; Homeostasis; Host resistance; Human; Immune; Immune response; Immunity; Infection; Inflammasome; Inflammatory; Inflammatory Bowel Diseases; Innate Immune Response; Knowledge; Leishmania; Leishmania major; Leishmaniasis; Link; Mediating; Metabolic Diseases; Modeling; Molecular; Molecular Target; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Multiple Sclerosis; Mus; Mycoses; Outcome; Parasites; Pathogen detection; Pathogenesis; Pathology; Pathway interactions; Persons; Phosphotransferases; Play; Predisposition; Protein Kinase Interaction; Publishing; RIPK1 gene; Receptor Activation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Surface; Virus Diseases; Work; adaptive immune response; combat; dectin 1; effective therapy; global health; mouse model; new therapeutic target; novel; novel therapeutics; obligate intracellular parasite; pathogen; receptor; response; restoration; sensor; skin disorder; targeted treatment; therapeutic target; treatment strategy

PROJECT SUMMARY Pathogen recognition receptors and their associated adaptors are essential for the prompt detection of pathogens and the subsequent initiation of effective host responses and restoration of homeostasis. Over the last decade, Nod-like receptors (NLRs) have been on the forefront of innate immune research, and several groundbreaking studies have been published, to which my research has contributed. Leishmania spp. are parasites with global health importance, yet the role of NLRs and their adaptors during Leishmania spp. infection has been an understudied area. Receptor interacting protein kinase 2 (RIPK2) is an essential adaptor downstream of cytoplasmic sensors NLRC1 and NLRC2, and play an important role in a wide variety of clinical settings including bacterial, viral and fungal infections, as well as non-infectious inflammatory diseases such as multiple sclerosis, inflammatory bowel disease and metabolic diseases. However, the role of RIPK2 during cutaneous leishmaniasis remain unknown. In this grant, we propose to investigate the precise cellular and molecular mechanisms involving RIPK2 during Leishmania major (L. major)-induced cutaneous disease. Our preliminary work has already elucidated several exciting features of the role of RIPK2 during L. major infection. We found that RIPK2- deficient mice are highly susceptible to L. major infection. Unexpectedly, mice deficient in NLRC2 or both NLRC1/NLRC2 are dispensable in L. major infection suggesting a novel sensor that function upstream of RIPK2. Moreover, RIPK2 interacted with CARD9 to provide protection against L. major. Based on these preliminary data, we propose that a novel Dectin-1/RIPK2/CARD9 signaling axis modulates anti-leishmanial immunity. Successful completion of this project will yield a better understanding of RIPK2 biology in general, unveil a novel pathway involving RIPK2 in signal transduction, and potentially identify therapeutic targets to ameliorate Leishmania spp.-associated pathology. 1

项目总结 病原体识别受体及其相关的适配器对于快速检测 病原体以及随后有效寄主反应的启动和内稳态的恢复。超过了 在过去的十年里，节点样受体(NLRs)一直处于先天免疫研究的前沿，有几个 开创性的研究已经发表，我的研究对此做出了贡献。利什曼原虫是 具有全球健康重要性的寄生虫，但NLR及其适配器在利什曼原虫中的作用。 感染一直是一个研究不足的领域。 受体相互作用蛋白激酶2(RIPK2)是细胞质感受器下游的一个重要接头 NLRC1和NLRC2，在各种临床环境中发挥重要作用，包括细菌、病毒和 真菌感染，以及非传染性炎症性疾病，如多发性硬化症、炎症性 肠道疾病和代谢性疾病。然而，RIPK2在皮肤利什曼病中的作用仍然存在。 未知。在这项资助中，我们建议研究精确的细胞和分子机制，包括 RIPK2在大利什曼原虫引起的皮肤病过程中。我们的前期工作已经 阐明了RIPK2在主要乳杆菌感染过程中所起作用的几个令人兴奋的特征。我们发现RIPK2- 基因缺陷的小鼠对主要乳杆菌的感染高度敏感。出乎意料的是，NLRC2基因缺陷或两者都缺乏的小鼠 NLRC1/NLRC2在大型乳杆菌感染中是必不可少的，这表明一种新的传感器作用于 RIPK2。此外，RIPK2与CARD9相互作用，对大斑狼疮具有保护作用。基于这些 初步数据，我们提出了一个新的Dectin-1/RIPK2/CARD9信号轴调节抗利什曼 豁免权。 这个项目的成功完成将使我们对RIPK2生物学有更好的了解，揭开了一个 RIPK2参与信号转导的新途径，并有可能确定改善的治疗靶点 利什曼原虫相关病理学。 1