Duong Nancy, Osborne Suzanne, Bustamante Víctor H, Tomljenovic Ana M, Puente José L, Coombes Brian K
Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
J Biol Chem. 2007 Nov 23;282(47):34077-84. doi: 10.1074/jbc.M707352200. Epub 2007 Sep 25.
The expression of bacterial virulence genes is tightly controlled by the convergence of multiple extracellular signals. As a zoonotic pathogen, virulence gene regulation in Salmonella enterica serovar Typhimurium must be responsive to multiple cues from the general environment as well as from multiple niches within animal and human hosts. Previous work has identified combined magnesium and phosphate limitation as an environmental cue that activates genes required for intracellular virulence. One unanswered question is how virulence genes that are expressed within the host are inhibited in non-host environments that satisfy the phosphate and magnesium limitation cues. We report here that thermosensing is the major mechanism controlling incongruous activation of the intracellular virulence phenotype. Bacteria grown at 30 degrees C or lower were unable to activate the intracellular type III secretion system even under strong inducing signals such as synthetic medium, contact with macrophages, and exposure to the murine gut. Thermoregulation was fully recapitulated in a Salmonella bongori strain engineered to contain the intracellular virulence genes of S. enterica sv. Typhimurium, suggesting that orthologous thermoregulators were available. Accordingly, virulence gene repression at the nonpermissive temperature required Hha and H-NS, two nucleoid-like proteins involved in virulence gene control. The use of combined environmental cues to control transcriptional "logic gates" allows for transcriptional selectivity of virulence genes that would otherwise be superfluous if activated in the non-host environment. Thus, thermosensing by Salmonella provides integrated control of host niche-specific virulence factors.
细菌毒力基因的表达受到多种细胞外信号汇聚的严格控制。作为一种人畜共患病原体，鼠伤寒沙门氏菌血清型鼠伤寒沙门氏菌中的毒力基因调控必须对来自一般环境以及动物和人类宿主内多个生态位的多种线索做出反应。先前的研究已经确定镁和磷酸盐联合限制是一种环境信号，可激活细胞内毒力所需的基因。一个尚未解决的问题是，在满足磷酸盐和镁限制信号的非宿主环境中，宿主内表达的毒力基因是如何被抑制的。我们在此报告，温度感应是控制细胞内毒力表型不一致激活的主要机制。即使在合成培养基、与巨噬细胞接触和暴露于小鼠肠道等强烈诱导信号下，在30摄氏度或更低温度下生长的细菌也无法激活细胞内III型分泌系统。在经过基因工程改造以包含鼠伤寒沙门氏菌血清型鼠伤寒沙门氏菌细胞内毒力基因的邦戈尔沙门氏菌菌株中，完全重现了温度调节，这表明存在直系同源的温度调节因子。因此，在非允许温度下的毒力基因抑制需要Hha和H-NS，这两种与毒力基因控制有关的类核蛋白。利用联合环境信号来控制转录“逻辑门”，可以实现毒力基因的转录选择性，否则这些基因在非宿主环境中被激活将是多余的。因此，沙门氏菌的温度感应提供了对宿主生态位特异性毒力因子的综合控制。
