Background

Salmonella enterica serovar Typhimurium, a non-typhoidal food-borne pathogen, causes acute enterocolitis, bacteremia, extraintestinal focal infections in humans. Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2) contribute to invading into host cellular cytosol, residing in Salmonella-containing vacuoles for intracellular survival, and inducing cellular apoptosis. This study aimed to better understand the mechanism underlying apoptosis in Salmonella-infected macrophages.

Methods

S. Typhimurium SL1344 was used to evaluate extrinsic and intrinsic apoptosis pathways in THP-1 monocyte-derived macrophages in response to Salmonella infection.

Results

Activated caspase-3-induced apoptosis pathways, including extrinsic (caspase-8-mediated) and intrinsic (caspase-9-mediated) pathways, in Salmonella-infected macrophages were verified. THP-1 cells with dysfunction of TLR-4 and TLR-5 and Salmonella SPI-1 and SPI-2 mutants were constructed to identify the roles of the genes associated with programmed cell death in the macrophages. Caspase-3 activation in THP-1 macrophages was induced by Salmonella through TLR-4 and TLR-5 signaling pathways. We also identified that SPI-1 structure protein PrgH and effectors SipB and SipD, but not SPI-2 structure protein SsaV, could induce apoptosis via caspase-3 activation and reduce the secretion of inflammation marker TNF-α in the Salmonella-infected cells. The two effectors also reduced the translocation of the p65 subunit of NF-κB into the nucleus and the expression of TNF-α, and then inflammation was diminished.

Conclusion

Non-typhoid Salmonella induced apoptosis of macrophages and thereby reduced inflammatory cytokine production through the expression of SPI-1. This mechanism in host–pathogen interaction may explain why Salmonella usually manifests as occult bacteremia with less systemic inflammatory response syndrome in the bloodstream infection of children.

中文翻译：

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在沙门氏菌感染的巨噬细胞中通过内在和外在途径激活沙门氏菌致病岛 1 效应子的细胞凋亡

背景

沙门氏菌鼠伤寒血清型是一种非伤寒食源性病原体，可引起人类急性小肠结肠炎、菌血症、肠外局灶性感染。沙门氏菌致病岛 1 和 2（SPI-1 和 SPI-2）有助于侵入宿主细胞胞质溶胶，驻留在含沙门氏菌的液泡中用于细胞内存活，并诱导细胞凋亡。本研究旨在更好地了解沙门氏菌感染巨噬细胞凋亡的机制。

方法

小号。Typhimurium SL1344 用于评估 THP-1 单核细胞衍生的巨噬细胞响应沙门氏菌感染的外在和内在凋亡途径。

结果

在沙门氏菌感染的巨噬细胞中，激活的 caspase-3 诱导的细胞凋亡途径，包括外在（caspase-8 介导的）和内在（caspase-9 介导的）途径得到验证。构建具有 TLR-4 和 TLR-5 功能障碍的 THP-1 细胞以及沙门氏菌SPI-1 和 SPI-2 突变体，以确定与巨噬细胞中程序性细胞死亡相关的基因的作用。沙门氏菌通过 TLR-4 和 TLR-5 信号通路诱导 THP-1 巨噬细胞中的 Caspase-3 活化。我们还发现 SPI-1 结构蛋白 PrgH 和效应子 SipB 和 SipD，但不是 SPI-2 结构蛋白 SsaV，可以通过 caspase-3 激活诱导细胞凋亡并减少沙门氏菌中炎症标志物 TNF-α 的分泌- 感染细胞。这两种效应物还减少了 NF-κB 的 p65 亚基向细胞核中的易位和 TNF-α 的表达，从而减轻了炎症。

结论

非伤寒沙门氏菌诱导巨噬细胞凋亡，从而通过 SPI-1 的表达减少炎性细胞因子的产生。这种宿主-病原体相互作用的机制可以解释为什么沙门氏菌在儿童血流感染中通常表现为隐匿性菌血症，全身炎症反应综合征较少。