Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell Host Microbe. 2014 Feb 12;15(2):203-13. doi: 10.1016/j.chom.2014.01.013.
Pathogens utilize features of the host response as cues to regulate virulence gene expression. Salmonella enterica serovar Typhimurium (ST) sense Toll-like receptor (TLR)-dependent signals to induce Salmonella Pathogenicity Island 2 (SPI2), a locus required for intracellular replication. To examine pathogenicity in the absence of such cues, we evaluated ST virulence in mice lacking all TLR function (Tlr2(-/-)xTlr4(-/-)xUnc93b1(3d/3d)). When delivered systemically to TLR-deficient mice, ST do not require SPI2 and maintain virulence by replicating extracellularly. In contrast, SPI2 mutant ST are highly attenuated after oral infection of the same mice, revealing a role for SPI2 in the earliest stages of infection, even when intracellular replication is not required. This early requirement for SPI2 is abolished in MyD88(-/-)xTRIF(-/-) mice lacking both TLR- and other MyD88-dependent signaling pathways, a potential consequence of compromised intestinal permeability. These results demonstrate how pathogens use plasticity in virulence strategies to respond to different host immune environments.
病原体利用宿主反应的特征作为线索来调节毒力基因表达。沙门氏菌肠亚种 Typhimurium (ST) 感知 Toll 样受体 (TLR) 依赖性信号，诱导沙门氏菌致病岛 2 (SPI2)，这是一个细胞内复制所必需的基因座。为了在没有这些线索的情况下研究致病性，我们评估了缺乏所有 TLR 功能的小鼠 (Tlr2(-/-)xTlr4(-/-)xUnc93b1(3d/3d)) 中的 ST 毒力。当全身性递送至 TLR 缺陷型小鼠时，ST 不需要 SPI2 并且通过在细胞外复制来保持毒力。相比之下，SPI2 突变 ST 在相同小鼠的口服感染后高度减毒，这表明 SPI2 在感染的早期阶段发挥作用，即使不需要细胞内复制。在缺乏 TLR 和其他 MyD88 依赖性信号通路的 MyD88(-/-)xTRIF(-/-) 小鼠中，这种对 SPI2 的早期需求被消除，这可能是由于肠道通透性受损所致。这些结果表明病原体如何利用毒力策略的可塑性来应对不同的宿主免疫环境。
