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

项目概要 病原体识别受体及其相关接头对于及时检测病原体至关重要 病原体以及随后启动有效的宿主反应和恢复体内平衡。超过 过去十年，Nod 样受体 (NLR) 一直处于先天免疫研究的前沿，并且有一些 开创性的研究已经发表，我的研究对此做出了贡献。利什曼原虫属是 寄生虫对全球健康具有重要意义，但 NLR 及其适配器在利什曼原虫属中的作用。 感染一直是一个未被充分研究的领域。 受体相互作用蛋白激酶 2 (RIPK2) 是细胞质传感器下游的重要适配器 NLRC1 和 NLRC2，在多种临床环境中发挥着重要作用，包括细菌、病毒和 真菌感染，以及非感染性炎症性疾病，如多发性硬化症、炎症 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。在这笔赠款中，我们建议研究涉及的精确细胞和分子机制 大型利什曼原虫（L.major）引起的皮肤病期间的 RIPK2。我们的前期工作已经 阐明了 RIPK2 在硕大利斯特菌感染过程中的作用的几个令人兴奋的特征。我们发现 RIPK2- 有缺陷的小鼠极易受到硕大利斯特氏菌感染。出乎意料的是，小鼠缺乏 NLRC2 或两者兼而有之 NLRC1/NLRC2 在 L. Major 感染中是可有可无的，这表明有一种新型传感器可以在 L. Major 感染的上游发挥作用。 RIPK2。此外，RIPK2 与 CARD9 相互作用以提供针对 L. Major 的保护。基于这些 根据初步数据，我们提出一种新的 Dectin-1/RIPK2/CARD9 信号轴调节抗利什曼原虫 免疫力。 该项目的成功完成将有助于人们更好地了解 RIPK2 生物学，并揭示 涉及 RIPK2 信号转导的新途径，并可能确定改善的治疗靶点 利什曼原虫相关病理学。 1

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