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: 10092450
• 负责人: Prajwal Gurung
• 金额: $ 51.25万
• 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/10092450
• 关键词: Adaptor Signaling Protein; Affect; Antifungal Agents; Area; BCL10 gene; Bacterial Infections; Basic Science; Biochemical; Biology; Cells; Clinical; Complex; Cutaneous Leishmaniasis; Data; Development; Disease; Etiology; Event; Family; Genetic; Goals; Grant; Homeostasis; Host resistance; Human; Immune; Immune response; Immunity; Infection; Inflammasome; Inflammatory; Inflammatory Bowel Diseases; Knowledge; Lead; Leishmania; Leishmania major; Leishmaniasis; Link; Mediating; Metabolic; 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; Phosphotransferases; Play; Predisposition; Protein Kinase; Publishing; RIPK1 gene; Receptor Activation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Surface; Virus Diseases; Work; adaptive immune response; base; 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

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

项目摘要 病原体识别受体及其相关的衔接子对于快速检测病原体是必不可少的。 病原体和随后启动有效的宿主反应和恢复体内平衡。来 近十年来，Nod-like受体（NLR）一直处于先天免疫研究的前沿， 一些开创性的研究已经发表，我的研究也对这些研究做出了贡献。利什曼是 寄生虫与全球健康的重要性，但在利什曼原虫的NLR及其适配器的作用。 感染一直是研究不足的领域。 受体相互作用蛋白激酶2（RIPK 2）是细胞质传感器下游的重要衔接子 NLRC 1和NLRC 2，并在各种各样的临床环境中发挥重要作用，包括细菌，病毒和 真菌感染以及非感染性炎性疾病如多发性硬化、炎性 肠道疾病和代谢疾病。然而，RIPK 2在皮肤利什曼病中的作用仍然存在， 未知在这项资助中，我们计划研究涉及以下方面的精确细胞和分子机制： RIPK 2在大型利什曼原虫（L.主要）引起的皮肤病。我们的前期工作已经 阐明了RIPK 2在L.严重感染我们发现RIPK 2- 缺陷型小鼠对L.严重感染出乎意料的是，缺乏NLRC 2或两者的小鼠 NLRC 1/NLRC 2在L.一种新型的传感器， RIPK2.此外，RIPK 2与CARD 9相互作用以提供抗L.少校基于这些 根据初步数据，我们提出一种新的Dectin-1/RIPK 2/CARD 9信号轴调节抗利什曼原虫的作用。 免疫力 这个项目的成功完成将使人们更好地了解RIPK 2生物学，揭示一个新的生物学模型。 涉及RIPK 2信号转导的新途径，并可能确定治疗靶点，以改善 利什曼原虫属-相关病理学 1