Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia; Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
Inflammatory Bowel Diseases Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
Cell Mol Gastroenterol Hepatol. 2023;16(6):985-1009. doi: 10.1016/j.jcmgh.2023.08.011. Epub 2023 Sep 1.
BACKGROUND & AIMS: MUC13 cell surface mucin is highly expressed on the mucosal surface throughout the intestine, yet its role against bacterial infection is unknown. We investigated how MUC13 impacts Salmonella typhimurium (S Tm) infection and elucidated its mechanisms of action.
Muc13 and wild-type littermate mice were gavaged with 2 isogenic strains of S Tm after pre-conditioning with streptomycin. We assessed clinical parameters, cecal histology, local and systemic bacterial load, and proinflammatory cytokines after infection. Cecal enteroids and epithelial cell lines were used to evaluate the mechanism of MUC13 activity after infection. The interaction between bacterial SiiE and MUC13 was assessed by using siiE-deficient Salmonella.
S Tm-infected Muc13 mice had increased disease activity, histologic damage, and higher local and systemic bacterial loads. Mechanistically, we found that S Tm binds to MUC13 through its giant SiiE adhesin and that MUC13 acts as a pathogen-binding decoy shed from the epithelial cell surface after pathogen engagement, limiting bacterial invasion. In addition, MUC13 reduces epithelial cell death and intestinal barrier breakdown by enhancing nuclear factor kappa B signaling during infection, independent of its decoy function.
We show for the first time that MUC13 plays a critical role in antimicrobial defense against pathogenic S Tm at the intestinal mucosal surface by both acting as a releasable decoy limiting bacterial invasion and reducing pathogen-induced cell death. This further implicates the cell surface mucin family in mucosal defense from bacterial infection.
黏蛋白 13（MUC13）是一种高度表达于整个肠道黏膜表面的细胞表面黏蛋白，但其在细菌感染中的作用尚不清楚。本研究旨在探讨 MUC13 对鼠伤寒沙门氏菌（S Tm）感染的影响，并阐明其作用机制。
在使用链霉素预处理后，经灌胃给予 Muc13 敲除和野生型同窝小鼠 2 种同源的 S Tm 菌株。感染后评估临床参数、盲肠组织学、局部和全身细菌负荷以及促炎细胞因子。使用肠类器官和上皮细胞系评估感染后 MUC13 活性的作用机制。通过使用 SiiE 缺陷型沙门氏菌评估细菌 SiiE 与 MUC13 之间的相互作用。
与野生型小鼠相比，S Tm 感染的 Muc13 敲除小鼠的疾病活动度、组织学损伤以及局部和全身细菌负荷均增加。机制上，我们发现 S Tm 通过其巨大的 SiiE 黏附素与 MUC13 结合，MUC13 在病原体结合后作为从上皮细胞表面释放的病原体结合诱饵，限制细菌入侵。此外，MUC13 通过增强感染过程中的核因子 kappa B 信号，减少上皮细胞死亡和肠道屏障破坏，而与其诱饵功能无关。
本研究首次表明，MUC13 通过充当可释放的诱饵限制细菌入侵和减少病原体诱导的细胞死亡，在肠道黏膜表面对致病性 S Tm 的抗菌防御中发挥关键作用。这进一步表明细胞表面黏蛋白家族在肠道防御细菌感染中具有重要作用。
