猪链球菌表面蛋白ZnMc诱导过度炎症反应的分子机制研究

Streptococcus suis (SS) is an important zoonotic pathogen, which severely threatens human health and swine industry. Excessive inflammation is not only an important reason for SS-caused death, but also an inducer of most other clinical symptoms caused by SS. However, the mechanism of SS-induced excessive inflammation remains unclear, which has become one of the most important problems in pathogenesis of SS. Our previous study indicated that the surface protein ZnMc of SS, with a strong pro-inflammatory activity, is an essential component of SS inducing excessive inflammation, and significantly impacts the pathogenicity of SS. However, its function mechanism remains unclear. Based on above findings, we will focus on the molecular basis and signal transduction pathways of SS-induced pro-inflammatory response to launch systematic research. This project aims to identify the critical structural domains, recognition receptors, intracellular adaptor proteins and transcription factors, which are responsible for the pro-inflammatory activity of ZnMc, thus clarify the molecular mechanism of ZnMc triggered inflammatory response. The obtained results could not only further reveal the mechanism of SS-induced excessive inflammation, but also lay the foundation for further researches on the pathogenesis of SS.

猪链球菌（Streptococcus suis, SS）是一种重要的人畜共患病病原，严重威胁着人类健康与养猪业。过度的炎症反应不仅是SS致死的重要原因，也是其众多临床症状的诱发因素，然而，目前SS诱导过度炎症反应的机理却仍然未知，已成为SS致病机制中急需解决的关键问题。前期研究证明SS表面蛋白ZnMc具有强烈的促炎活性，是SS引起过度炎症反应的必要组分，能够显著影响SS的致病力，但其作用机制尚不清楚。基于此，本项目将围绕ZnMc激活炎性应答的分子基础与信号转导通路展开系统的研究，旨在挖掘ZnMc促炎活性所依赖的关键结构域、识别受体、胞内接头蛋白以及转录调控因子，从而阐明ZnMc激活炎性应答的分子机制，研究结果不仅能进一步揭示SS诱导过度炎症反应的机理，同时还能为全面理解SS的致病机制奠定基础。

猪链球菌（Streptococcus suis, SS）是一种重要的人畜共患病病原，严重威胁着人类健康与养猪业。过度的炎症反应不仅是SS致死的重要原因，也是其众多临床症状的诱发因素，然而，目前SS诱导过度炎症反应的机理却仍然未知，已成为SS致病机制中急需解决的关键问题之一。在本项目中，我们发现SS的胞外蛋白HP1717（即ZnMc）对RAW 264.7具有强烈的促炎作用,且该促炎作用具有剂量依赖性与热失活特性，是SS引起过度炎症反应的必要组分。为了研究HP1717是否与SS的致病力相关，我们构建了其缺失突变菌株，并通过体外和体内实验，证实HP1717的缺失能够显著降低SS的毒力，表明HP1717是SS的一个重要的毒力相关因子。随后，为了解析HP1717诱导过度炎性应答的机制，我们继续对HP1717的炎性识别受体和信号转导通路进行了分析，结果证实HP1717的促炎作用主要依赖于TLR2的识别，以及NF-κB和ERK1/2的磷酸化。总起来说，本项目证实了促炎蛋白HP1717是SS的一个新的毒力相关因子，并且解析了其促炎分子机制，研究结果不仅进一步揭示了SS诱导过度炎症反应的机理，同时还为全面理解SS的致病机制奠定了基础。