鱼源鲁氏耶尔森菌STIR-3抑制NLRP3炎性小体活化及其介导的免疫逃避机制研究

免疫逃避是强致病性微生物的重要特征，其中以主动干扰宿主免疫调控更具威胁性。项目前期研究发现：鱼源强毒力鲁氏耶尔森菌可利用其致病岛ICE(r2)编码的毒力蛋白STIR-3，竞争性结合TLR-2和TLR-4的接头蛋白MyD88，主动干扰宿主天然免疫，实现细菌致病性。然而，TLR-2和TLR-4一般感应胞外模式分子，该病原胞内免疫逃避机制尚不明确。根据模式识别特征的相似性，我们提出STIR-3可能干扰NLRP3炎性小体活化并实现其致病性的假设。本项目将通过体内和体外感染试验，结合免疫学方法，探索STIR-3对NLRP3炎性小体信号通路的影响，阐明STIR-3对胞内天然免疫信号的相关调控机制。本研究成果将为鱼源强毒力鲁氏耶尔森菌的致病性来源提供直接证据，突破该病原免疫逃避的研究瓶颈，有助于水产养殖中更具针对性地控制鲁氏耶尔森菌感染。

Immune evasion is an important feature of highly pathogenic microorganisms, and active interference with the host immune regulation represents a means by which the pathogen can avoid harm. Preliminary research from our group has found that highly virulent fish-derived Yersinia ruckeri can use its pathogenicity island ICE(r2) encoded virulence protein (STIR-3) to competitively bind to the Toll-like receptor adaptor protein (MyD88), actively interfering with the host’s natural immunity, resulting in bacterial pathogenicity. However, Toll-like receptors (TLR-2 and TLR-4) only sense extracellular pattern molecules, and the intracellular immune evasion mechanism used by this pathogen remains unclear. Therefore, we propose that STIR-3 may interfere with the recognition of intracellular pattern molecules via the NLRP3 inflammasome, thereby causing its pathogenicity. We will go on to further explore the effect of STIR-3 on the NLRP3 inflammasome-mediated intracellular innate immune signals using both in vivo and in vitro infection tests, combined with immunological methods. We will also explore the co-localization and interactional relationship between STIR-3 and the NLRP3 inflammasome at the subcellular level to clarify the inhibitory effect of STIR-3 on intracellular natural immune signals and related regulatory mechanisms. Results from this study will provide direct evidence for the pathogenicity of highly virulent fish-derived Yersinia ruckeri and highlight the potential threat of active immune evasion and help to develop a more targeted approach for the prevention and control of such microbial infections.