RIP1/RIP3介导的细胞程序性坏死是一类新发现的可受调控的细胞死亡方式，在一些感染性疾病中呈现出重要作用。我们在钩端螺旋体（钩体）的致病机制研究中发现钩体可引起巨噬细胞程序性坏死。动物实验结果显示，RIP1髓系条件性敲除小鼠或RIP3敲除小鼠感染钩体后与WT小鼠相比，呈现出血、黄疸症状减轻，血和组织中钩体载量下降等现象。因此我们推测钩体感染后激活巨噬细胞RIP1/RIP3介导的程序性坏死，大量免疫活性细胞死亡及坏死引起的损伤相关分子模式（DAMPs）的释放，可最终导致钩体清除率下降，组织损伤、感染加重。鉴于程序性坏死在钩体感染中的作用及具体机制尚不明晰，本项目拟在细胞和动物模型两个层面研究RIP1/RIP3介导的程序性坏死在钩体感染中的作用机制。目的是理解钩体如何调控细胞程序性坏死及细胞程序性坏死对宿主天然免疫抗钩体感染的影响与作用。研究成果将为钩体致病机制研究提供新线索和依据。

RIP1-RIP3-mediated necroptosis is a newly discovered class of regulated cell death that plays an important role in some infectious diseases. In our preliminary study on the pathogenesis of leptospirosis, we found that Leptospira can induce murine macrophage necroptosis in vitro. Then the animal study showed that RIP3-/- or LysM-cre RIP1-/- mice infected with Leptospira have less bleeding, jaundice and decreased Leptospira load in blood and tissue compared with WT mice. Therefore, we hypothesize that macrophage undergo RIP1/RIP3 mediated necroptosis after infected with Leptospira. The in vivo depletion of immune-activated macrophages and the release of danger-associated molecular patterns (DAMPs) following necroptosis after Leptospira infection could eventually lead to destroy the bactericidal ability and cause tissue damage. Since the mechanism of necroptosis in leptospirosis is not clear, this project intends to study the mechanism of RIP1-RIP3-mediated necroptosis in Leptospira infection in both cellular and animal models. We also hope to understand how Leptospira regulates cell necroptosis and how necroptosis affects host innate immunity against Leptospira. The research results will provide new clues for the study of the pathogenesis of Leptospira infection.