<b>TolC facilitates the Intracellular Survival and Immunomodulation of </b><b><i>Salmonella</i></b><b> Typhi in Human Host Cells</b>

<b>Introduction:</b> <i>Salmonella enterica</i> serovar Typhi (<i>S</i>. Typhi) causes typhoid fever, a systemic infection that affects millions of people worldwide. <i>S</i>. Typhi can invade and survive within host cells, such as intestinal epithelial cells and macrophages, by modulating their immune responses. However, the immunomodulatory capability of <i>S</i>. Typhi in relation to TolC-facilitated efflux pump function remains unclear. <b>Methods: </b>The role of TolC, an outer membrane protein that facilitates efflux pump function, in the invasion and immunomodulation of <i>S</i>. Typhi, was studied in human intestinal epithelial cells and macrophages. The <i>tolC</i> deletion mutant of <i>S</i>. Typhi was compared with the wild-type and its complemented strain in terms of their ability to invade epithelial cells, survive and induce cytotoxicity in macrophages, and elicit proinflammatory cytokine production in macrophages. <b>Results:</b> The <i>tolC</i> mutant, which has a defective outer membrane, was impaired in invading epithelial cells compared to the wild-type strain, but the intracellular presence of the <i>tolC</i> mutant exhibited greater cytotoxicity and induced higher levels of proinflammatory cytokines (<i>IL-1β</i> and <i>IL-8</i>) in macrophages compared to the wild-type strain. These effects were reversed by complementing the <i>tolC</i> mutant with a functional <i>tolC</i> gene. <b>Discussion:</b> Our results suggest that TolC plays a role in <i>S</i>. Typhi to efficiently invade epithelial cells and suppress host immune responses during infection. TolC may be a potential target for the development of novel therapeutics against typhoid fever.

<b>引言：</b> <i>肠炎沙门氏菌伤寒血清型（<i>Salmonella enterica</i> serovar Typhi，下称<i>S</i>. Typhi）</i>可引发伤寒，这是一种波及全球数百万人群的全身性感染。<i>S</i>. Typhi能够侵入并存活于宿主细胞（如肠上皮细胞与巨噬细胞），通过调控宿主免疫应答实现定植与存活。然而，伤寒沙门氏菌的免疫调控能力与TolC介导的外排泵（efflux pump）功能之间的关联仍不明确。<b>研究方法：</b> 本研究以介导外排泵（efflux pump）功能的外膜蛋白TolC为研究对象，在人类肠上皮细胞与巨噬细胞模型中探究<i>S</i>. Typhi的侵袭与免疫调控过程中TolC所发挥的作用。将<i>S</i>. Typhi的<i>tolC</i>基因缺失突变株与野生型菌株、互补菌株进行对比，分析三者在上皮细胞侵袭能力、巨噬细胞内存活与细胞毒性诱导能力，以及巨噬细胞促炎细胞因子产生能力方面的差异。<b>研究结果：</b> 外膜存在缺陷的<i>tolC</i>突变株，其侵袭上皮细胞的能力较野生型菌株受损；但相较于野生型菌株，胞内的<i>tolC</i>突变株在巨噬细胞中展现出更强的细胞毒性，并可诱导更高水平的促炎细胞因子（白细胞介素1β（IL-1β）与白细胞介素8（IL-8））的产生。上述效应可通过向<i>tolC</i>突变株导入功能性<i>tolC</i>基因进行互补逆转。<b>讨论：</b> 本研究结果表明，TolC在<i>S</i>. Typhi高效侵袭上皮细胞以及抑制感染过程中的宿主免疫应答中发挥关键作用。TolC或可成为开发新型抗伤寒治疗药物的潜在靶点。

搜集汇总

背景与挑战

背景概述

该数据集研究伤寒沙门氏菌（Salmonella Typhi）中TolC蛋白的功能，重点关注其在人类宿主细胞（如肠上皮细胞和巨噬细胞）中的入侵、存活和免疫调节作用。通过比较野生型、tolC缺失突变体和互补菌株，发现TolC缺失会降低细菌入侵上皮细胞的能力，但增强在巨噬细胞内的细胞毒性和促炎细胞因子（如IL-1β和IL-8）的产生，表明TolC有助于细菌有效入侵并抑制宿主免疫反应。数据集包括实验数据如入侵、LDH和Tunel检测，并支持TolC作为潜在治疗靶点，为伤寒热的新疗法开发提供依据。