Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan; Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
J Microbiol Immunol Infect. 2021 Aug;54(4):616-626. doi: 10.1016/j.jmii.2020.02.008. Epub 2020 Feb 26.
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.
S. Typhimurium SL1344 was used to evaluate extrinsic and intrinsic apoptosis pathways in THP-1 monocyte-derived macrophages in response to Salmonella infection.
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.
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.
鼠伤寒沙门氏菌血清型 Typhimurium 是一种非伤寒食源性病原体，可引起人类急性肠炎、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，在沙门氏菌包含的空泡中存活，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中细胞凋亡的机制。
使用鼠伤寒沙门氏菌 SL1344 评估 THP-1 单核细胞衍生巨噬细胞中沙门氏菌感染诱导的细胞外和细胞内凋亡途径。
证实了沙门氏菌感染巨噬细胞中激活的 caspase-3 诱导的凋亡途径，包括细胞外（caspase-8 介导）和细胞内（caspase-9 介导）途径。构建了 TLR-4 和 TLR-5 功能失调的 THP-1 细胞和沙门氏菌 SPI-1 和 SPI-2 突变体，以确定与编程性细胞死亡相关的基因在巨噬细胞中的作用。通过 TLR-4 和 TLR-5 信号通路，沙门氏菌诱导 THP-1 巨噬细胞中 caspase-3 的激活。我们还发现，SPI-1 结构蛋白 PrgH 和效应蛋白 SipB 和 SipD，但不是 SPI-2 结构蛋白 SsaV，可通过 caspase-3 激活诱导凋亡，并减少沙门氏菌感染细胞中炎症标志物 TNF-α的分泌。这两个效应蛋白还减少了 NF-κB p65 亚基向核内的易位和 TNF-α的表达，从而减轻了炎症反应。
非伤寒沙门氏菌通过 SPI-1 的表达诱导巨噬细胞凋亡，从而减少炎症细胞因子的产生。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和较少的全身炎症反应综合征。
