HCA2在沙门菌黏膜感染中的作用及机制研究

Salmonella is a most important food-borne pathogen that causes disease in human and many kinds of animals with high morbidity and mortality resulting in a huge burden to public health and animal husbandry worldwide. Recently, probiotic bacteria and its metabolites remain an appealing measure for the therapeutic potential and several of which have a beneficial effect in limiting Salmonella colonization. HCA2 is a metabolite receptor and activated by butyric which is produced in large quantities by bacterial fermentation, whereas its ability to protect against bacterial infection remains to be unveiled. To explore the function of HCA2 in regulating host mucosal immune response against Salmonella infection, this study intends to analyze the susceptibility of both WT and HCA2-deficient mice to Salmonella mucosal infection. Subsequently, the intestinal barrier function is analyzed via examining the rate of Salmonella translocated the single epithelial layer with HCA2-deficient mice in vivo and HCA2-overexpressing cell in vitro respectively. Finally, this study will focus on how does the HCA2 signaling pathway regulate the intestinal barrier function to protect against Salmonella infection. This study will uncover that HCA2 is a key receptor that connect the gut microbial to the intestinal barrier function responsible for the defense against Salmonella mucosal infection and targeting the HCA2 signaling pathway will be a new theoretic for the design of probiotics against Salmonella infection.

沙门菌是目前世界范围内最重要的食源性病原之一，能够感染人和多种动物，引起很高的发病率和死亡率，对畜牧业的发展和人类的健康构成严重的威胁。近年来，肠道微生物及其代谢产物在疾病预防中的作用越来越受重视，多种肠道微生物能够限制沙门菌感染。HCA2是一种代谢受体，细菌发酵产物丁酸是其配体，其在调控细菌感染方面的研究进展甚微。本项目拟通过建立沙门菌肠炎模型，基于HCA2-/-小鼠，分析WT和HCA2-/-小鼠对沙门菌黏膜感染的易感性；随后分别通过在体动物实验和体外构建稳定过表达HCA2的细胞系分析HCA2对沙门菌跨上皮细胞层扩散至黏膜下层的影响；并通过体内、体外两种途径分析HCA2信号调节肠道屏障功能，限制沙门菌扩散的机制。通过本项目的研究阐明HCA2是连接肠道菌群和肠道屏障功能的纽带，在限制沙门菌黏膜感染中起重要作用，为研发靶向HCA2信号的抗沙门菌感染的微生态制剂提供理论支持。

沙门菌是造成人类食源性疾病的主要病原之一，严重危害家畜和人类健康。伤寒沙门菌是威胁发展中国家健康的主要问题，每年感染超过21万人。HCA2的功能除了早期的抗脂解作用，还能够参与炎症的调节。本项目系统的研究了HCA2在鼠伤寒沙门菌黏膜感染中的作用及机制。首先构建野生型（WT）和HCA2基因缺失型（HCA2-/-）小鼠沙门菌肠炎模型，分析HCA2在沙门菌感染中的作用。结果发现与 WT 小鼠相比，HCA2-/-小鼠更为易感。这一结果表明HCA2有助于机体抵抗沙门菌黏膜感染。为了揭示 HCA2限制沙门菌黏膜感染表型的机制，我们分析了HCA2对肠黏膜物理屏障、微生物屏障以及炎症反应的影响。结果发现HCA2能够调节肠道菌群结构限制沙门菌诱导的肠炎；早期感染和全身系统感染模型表明HCA2所塑造的肠道菌群不影响感染早期沙门菌的肠腔定殖，而是通过影响中性粒细胞的募集抑制沙门菌黏膜感染。这些结果揭示了HCA2、肠道菌群和免疫系统之间的关系，为沙门菌感染肠炎的防治提供了新思路。