肠道病毒激活肠上皮内质网应激调控肠道黏膜屏障-免疫应答的机制研究

肠道病毒流行已造成当今人类公共卫生安全新的威胁。肠道病毒经粪口途径感染肠道黏膜表面，随后传播和扩散至目标组织导致临床疾病。肠黏膜屏障是抵御肠道病毒早期感染的关键环节，而肠上皮内质网稳态对维持肠道平衡尤为重要。肠道病毒感染过程中，肠上皮细胞内质网稳态对肠道黏膜屏障及免疫应答的作用仍未弄清。我们前期研究发现，在细胞和组织水平中，肠道病毒（包括人肠道病毒71型）感染肠上皮细胞诱导内质网应激，并增加肠上皮细胞黏液蛋白表达；进一步证实肠道病毒早期感染肠上皮细胞过程中，通过激活TLR3/IRF1信号通路，特异性诱导III型干扰素抗病毒免疫反应。在此基础上，我们将进一步研究肠道病毒激活肠上皮细胞内质网应激，进而介导肠上皮屏障及黏液表达，最终调控肠上皮细胞和肠道微环境免疫应答。本项目旨在阐明肠道病毒调控肠道免疫应答过程中新的分子机理和作用机制，为有效预防和治疗肠道病毒感染及相关疾病提供科学依据和药物靶标。

The epidemiology of Enteroviruses gives rise to an emerging threat to the safety of human public health worldwide nowadays. Enteroviruses are primarily transmitted through the fecal–oral route and target the intestinal epithelium, subsequently disseminate into secondary target tissues to cause clinical diseases. Therefore, the intestinal mucosal barrier acts as a key defense during Enteroviruses early infection. In this situation, the endoplasmic reticulum (ER) homeostasis in intestinal epithelial cells (IECs) plays an important role to maintain the balance in gut. However, the function of ER homeostasis in IECs upon Enterovirus infections involved in the regulation of the intestinal mucosal barrier or/and immune response remains unclear. In our previous studies in the cultured human IECs, mouse tissues, and human clinical intestine specimens, we revealed that Enterovirus (including human enterovirus 71, EV71) infections induced ER stress and mucins expression in IECs. Moreover, Enterovirus infections activated the Toll-like receptor 3/Interferon regulatory factor 1 (TLR3/IRF1) signaling pathway, leading to the dominant production of type III interferons (IFN-λ1 and IFN-λ2/3) in IECs, which in turn triggered intrinsically antiviral responses against Enterovirus replications. Based on this, we will further explore that Enteroviruses induce ER stress in IECs, mediating the alterations of intestinal mucosal barrier as well as mucins expression, which remodels the immune responses in the intestinal epithelial cells and microenvironment. Our proposal focuses on clarifying a novel mechanism underlying the regulation of Enterovirus-induced ER stress in IECs on intestinal mucosal immune response, which provides foundations and strategies for developing the prevention and treatment in Enterovirus infections and clinical associated diseases.