PDF(Pubmed)
Abstract：
Salmonella enterica serovar Typhimurium (S. Typhimurium), an important foodborne pathogen, causes diarrheal illness and gastrointestinal diseases. S. Typhimurium survives and replicates in phagocytic and non-phagocytic cells for acute or chronic infections. In these cells, S. Typhimurium resides within Salmonella-containing vacuoles (SCVs), in which the phosphate (Pi) concentration is low. S. Typhimurium senses low Pi and expresses virulence factors to modify host cells. However, the mechanism by which host cells reduce the Pi concentration in SCVs is not clear. In this study, we show that through the TLR4-MyD88-NF-κB signaling pathway, S. Typhimurium upregulates PIT1, which in turn transports Pi from SCVs into the cytosol and results in Pi starvation in SCVs. Immunofluorescence and western blotting analysis reveal that after the internalization of S. Typhimurium, PIT1 is located on SCV membranes. Silencing or overexpressing PIT1 inhibits or promotes Pi starvation, Salmonella pathogenicity island-2 (SPI-2) gene expression, and replication in SCVs. The S. Typhimurium ΔmsbB mutant or silenced TLR4-MyD88-NF-κB pathway suppresses the expression of the SPI-2 genes and promotes the fusion of SCVs with lysosomes. Our results illustrate that S. Typhimurium exploits the host innate immune responses as signals to promote intracellular replication, and they provide new insights for the development of broad-spectrum therapeutics to combat bacterial infections.
摘要：
肠病沙门氏菌（S.鼠伤寒)，一种重要的食源性病原体，引起腹泻和胃肠道疾病。对于急性或慢性感染，鼠伤寒沙门氏菌在吞噬细胞和非吞噬细胞中存活和复制。在这些细胞中,鼠伤寒沙门氏菌位于含沙门氏菌的液泡（SCV）内，其中磷酸盐(Pi)浓度低。鼠伤寒沙门氏菌感知低Pi并表达毒力因子以修饰宿主细胞。然而,宿主细胞降低SCV中Pi浓度的机制尚不清楚。在这项研究中,我们发现通过TLR4-MyD88-NF-κB信号通路,鼠伤寒沙门氏菌上调PIT1，PIT1又将Pi从SCV转运到细胞质中，并导致SCV中的Pi饥饿。免疫荧光和免疫印迹分析显示，鼠伤寒沙门氏菌内化后，PIT1位于SCV膜上。沉默或过度表达PIT1抑制或促进Pi饥饿，沙门氏菌致病性岛-2(SPI-2)基因表达,和SCV中的复制。鼠伤寒沙门氏菌ΔmsbB突变体或沉默的TLR4-MyD88-NF-κB途径抑制SPI-2基因的表达并促进SCV与溶酶体的融合。我们的结果表明，鼠伤寒沙门氏菌利用宿主先天免疫反应作为促进细胞内复制的信号，它们为开发对抗细菌感染的广谱疗法提供了新的见解。
