Derepression of Salmonella pathogenicity island 1 genes within macrophages leads to rapid apoptosis via caspase‐1‐ and caspase‐3‐dependent pathways
Derepression of Salmonella pathogenicity island 1 genes within macrophages leads to rapid apoptosis via caspase‐1‐ and caspase‐3‐dependent pathways
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DOI：
10.1111/j.1462-5822.2004.00435.x
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发表时间：
2004-08
影响因子：
3.4
通讯作者：
A. Takaya;A. Suzuki;Y. Kikuchi;M. Eguchi;E. Isogai;T. Tomoyasu;Tomoko Yamamoto
中科院分区：
文献类型：
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作者：
A. Takaya;A. Suzuki;Y. Kikuchi;M. Eguchi;E. Isogai;T. Tomoyasu;Tomoko Yamamoto
据报道，沙门氏菌血清型鼠伤寒沙门氏菌在感染后14小时内通过半胱天冬酶1依赖性机制诱导感染的巨噬细胞凋亡。在这里，我们证明了鼠伤寒血清型中Lon蛋白酶的耗竭通过涉及半胱天冬酶-1和-3的机制诱导巨噬细胞快速和大量的凋亡。这种过度诱导的细胞凋亡被废除的破坏invF，这是所需的沙门氏菌致病岛1（SPI 1）基因的表达。巨噬细胞吞噬后，SPI 1转录的中心调节因子hilA的表达受到抑制，但当ΔLon突变体在巨噬细胞内生长时，该基因持续表达，因此SPI 1蛋白积累。因此，ΔLon突变体诱导的巨噬细胞凋亡增加可能是由于SPI 1基因在正常情况下受到抑制的条件下持续表达所致。一旦沙门氏菌建立了全身性感染，生物体所依赖的巨噬细胞的过度凋亡将对病原体有害。因此，可能需要Lon蛋白酶来充分抑制细胞凋亡，以允许细菌有时间复制、逃逸和侵入新的巨噬细胞。
Salmonella enterica serovar Typhimurium has been reported to induce apoptosis in infected macrophages within 14 h from the time of infection by a caspase‐1‐dependent mechanism. Here, we demonstrate that depletion of Lon protease in serovar Typhimurium induces rapid and massive apoptosis in macrophages by a mechanism involving both caspases‐1 and ‐3. This excessive induction of apoptosis was abrogated by disruption of invF, which is required for the expression of the Salmonella pathogenicity island 1 (SPI1) genes. Expression of hilA, a central regulator of SPI1 transcription, was repressed in the macrophages after phagocytosis, but this gene was continuously expressed when the ΔLon mutant grew within the macrophages, so the SPI1 proteins accumulated. Thus, the increase in macrophage apoptosis induced by the ΔLon mutant could result from continued expression of SPI1 genes under conditions where they are normally repressed. Once Salmonella has established a systemic infection, excess apoptosis of macrophages cells upon which the organism is reliant would be detrimental to the pathogen. Therefore, the Lon protease may be required to suppress apoptosis sufficiently to allow time for the bacterium to replicate, escape and invade new macrophages.