Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, California, United States of America.
PLoS Pathog. 2009 Nov;5(11):e1000671. doi: 10.1371/journal.ppat.1000671. Epub 2009 Nov 26.
Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time despite the presence of a robust immune response. Chronically infected hosts are asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. We show that the bacterial effector protein SseI (also called SrfH), which is translocated into host cells by the Salmonella Pathogenicity Island 2 (SPI2) type III secretion system (T3SS), is required for Salmonella typhimurium to maintain a long-term chronic systemic infection in mice. SseI inhibits normal cell migration of primary macrophages and dendritic cells (DC) in vitro, and such inhibition requires the host factor IQ motif containing GTPase activating protein 1 (IQGAP1), an important regulator of cell migration. SseI binds directly to IQGAP1 and co-localizes with this factor at the cell periphery. The C-terminal domain of SseI is similar to PMT/ToxA, a bacterial toxin that contains a cysteine residue (C1165) that is critical for activity. Mutation of the corresponding residue in SseI (C178A) eliminates SseI function in vitro and in vivo, but not binding to IQGAP1. In addition, infection with wild-type (WT) S. typhimurium suppressed DC migration to the spleen in vivo in an SseI-dependent manner. Correspondingly, examination of spleens from mice infected with WT S. typhimurium revealed fewer DC and CD4(+) T lymphocytes compared to mice infected with Delta sseI S. typhimurium. Taken together, our results demonstrate that SseI inhibits normal host cell migration, which ultimately counteracts the ability of the host to clear systemic bacteria.
肠沙门氏菌的宿主适应株会引起全身感染，并能在存在强大免疫反应的情况下长期在体内持续存在。慢性感染的宿主无症状，并通过细菌粪便排出将疾病传播给未感染的宿主，因此成为疾病的重要储存库。我们表明，细菌效应蛋白 SseI（也称为 SrfH），通过沙门氏菌致病性岛 2（SPI2）III 型分泌系统（T3SS）易位进入宿主细胞，是鼠伤寒沙门氏菌在小鼠体内维持长期慢性全身性感染所必需的。SseI 在体外抑制原代巨噬细胞和树突状细胞（DC）的正常细胞迁移，这种抑制需要宿主 IQ 基序包含 GTPase 激活蛋白 1（IQGAP1），这是细胞迁移的重要调节因子。SseI 直接与 IQGAP1 结合，并与该因子在细胞外周共定位。SseI 的 C 末端结构域类似于 PMT/ToxA，一种细菌毒素，含有一个对活性至关重要的半胱氨酸残基（C1165）。SseI 中相应残基（C178A）的突变消除了 SseI 在体外和体内的功能，但不影响与 IQGAP1 的结合。此外，野生型（WT）鼠伤寒沙门氏菌的感染以 SseI 依赖的方式抑制 DC 向脾脏的体内迁移。相应地，与感染 WT 鼠伤寒沙门氏菌的小鼠相比，感染 Delta sseI 鼠伤寒沙门氏菌的小鼠脾脏中的 DC 和 CD4+T 淋巴细胞更少。总之，我们的结果表明 SseI 抑制正常的宿主细胞迁移，这最终抵消了宿主清除全身细菌的能力。
