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: 10377313
• 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/10377313
• 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; Persons; 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适配器对于迅速检测至关重要 病原体以及随后的有效宿主反应和稳态的恢复。在 最近十年，点头样受体（NLR）一直处于先天免疫研究的最前沿，有几个 开创性的研究已经发表，我的研究为此做出了贡献。利什曼尼亚属。是 具有全球健康重要性的寄生虫，但Leishmania spp期间NLR及其适配器的作用。 感染一直是一个研究的区域。 受体相互作用蛋白激酶2（RIPK2）是细胞质传感器下游必需的适配器 NLRC1和NLRC2，在各种临床环境中起着重要作用，包括细菌，病毒和 真菌感染以及非感染性炎症性疾病，例如多发性硬化症，炎症 肠病和代谢疾病。但是，RIPK2在皮肤利什曼病中的作用仍然存在 未知。在这笔赠款中，我们建议研究涉及的精确细胞和分子机制 利什曼尼亚大调（L. major）诱发的皮肤病期间的RIPK2。我们的初步工作已经 阐明了RIPK2在主要感染过程中的作用的几个令人兴奋的特征。我们发现Ripk2- 缺乏小鼠非常容易受到主要感染的影响。出乎意料的是，NLRC2或两者都缺乏小鼠 NLRC1/NLRC2在L.主要感染中是可分配的 RIPK2。此外，RIPK2与Card9进行了互动，以防止L. Major。基于这些 初步数据，我们建议一种新型的Dectin-1/ripk2/card9信号轴调节反leishmanial 免疫。 成功完成该项目将对RIPK2生物学有更好的了解，揭开 涉及RIPK2信号转导的新途径，并有可能识别改善的治疗靶标 利什曼原虫属于相关病理学。 1