Invasion and intracellular replication of Salmonella Typhimurium in epithelial cells

鼠伤寒沙门氏菌对上皮细胞的侵袭和细胞内复制

• 批准号: 10927782
• 负责人: Olivia Steele-Mortimer
• 金额: $ 96.58万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927782
• 关键词: Acute; Animals; Bacteria; Biological Models; Biomedical Engineering; Cattle; Cells; Chemoreceptors; Chemotaxis; Chronic; Cytolysis; Cytosol; Disease; Enterocolitis; Environment; Epithelial Cells; Feces; Fluorescence; Gastrointestinal tract structure; Genetic Transcription; Goals; Growth; Human; In Vitro; Infection; Invaded; Mammalian Cell; Mediating; Modeling; Molecular; Mus; Natural Resistance; Pathogenesis; Pathway interactions; Play; Population; Predisposition; Reporting; Role; Salmonella; Salmonella enterica; Salmonella typhimurium; Signal Pathway; Swimming; System; Type III Secretion System Pathway; Typhoid Fever; Virulence; cell motility; chronic infection; human model; human pathogen; in vitro Model; intestinal epithelium; lytic gene expression; oral infection; pathogen; protein expression

Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) is a common cause of enterocolitis in humans and cattle but causes a systemic, typhoid-like, disease in susceptible mice. This facultative intracellular pathogen invades non-phagocytic cells, particularly intestinal epithelial cells. We have previously shown that efficient invasion of intestinal epithelial cells is facilitated by smooth swimming mediated by the chemoreceptor, McpC. We are now studying the role of a second chemoreceptor, McpA, that is co-expressed with McpC. Intracellular replication occurs within the SCV and within the cytosol, bacterial growth rates and transcriptional status within these two intracellular niches are quite different. In particular, the T3SS1 is functionally active in the cytosolic bacteria whereas the T3SS2 is functionally active in the vacuolar bacteria. Thus, each of the T3SS systems are functional in the intracellular environment albeit in different niches. Previously we have developed an environmental autolytic strain, that lysis in the cytosol of mammalian cells, to study the role of the cytosolic population. Using bioengineered Salmonella to either report their intracellular localization (fluorescence protein expression) or to lyse in specific intracellular compartments (lytic gene expression) we are studying how Salmonella intersect signaling pathways in infected epithelial cells and how this impacts survival of the infected host cell or bystanders. Oral infection of naturally resistant mice (e.g. 129X1/SvJ) with Salmonella Typhimurium leads to chronic infection with a small percentage of animals shedding high levels of Salmonella in their feces (super shedders). We are using this model to investigate the factors involved in shedding and persistence and the role played by intestinal epithelial cells.

鼠伤寒沙门氏菌（Salmonella Typhimurium）是人类和牛小肠结肠炎的常见原因，但在易感小鼠中引起全身性伤寒样疾病。这种兼性细胞内病原体侵入非吞噬细胞，特别是肠上皮细胞。我们以前已经表明，肠上皮细胞的有效入侵是由化学感受器，McpC介导的顺利游泳促进。我们现在正在研究与McpC共表达的第二种化学感受器McpA的作用。细胞内复制发生在SCV和胞质内，这两个细胞内小生境内的细菌生长速率和转录状态是完全不同的。特别地，T3 SS 1在胞质细菌中具有功能活性，而T3 SS 2在空泡细菌中具有功能活性。因此，每个T3 SS系统都在细胞内环境中发挥作用，尽管在不同的生态位中。以前，我们已经开发了一种环境自溶菌株，在哺乳动物细胞的胞质溶胶中裂解，以研究胞质群体的作用。使用生物工程沙门氏菌报告其细胞内定位（荧光蛋白表达）或裂解在特定的细胞内隔室（裂解基因表达），我们正在研究沙门氏菌如何在感染的上皮细胞中交叉信号通路，以及这如何影响感染的宿主细胞或旁观者的生存。鼠伤寒沙门氏菌经口感染天然耐药小鼠（例如129 X1/SvJ）导致慢性感染，其中一小部分动物在其粪便中排出高水平的沙门氏菌（超级排出者）。我们正在使用这个模型来研究脱落和持久性的相关因素以及肠上皮细胞所起的作用。

项目成果

A second wave of Salmonella T3SS1 activity prolongs the lifespan of infected epithelial cells.

• DOI: 10.1371/journal.ppat.1006354
• 发表时间: 2017-04
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Finn CE;Chong A;Cooper KG;Starr T;Steele-Mortimer O
• 通讯作者: Steele-Mortimer O

The bimodal lifestyle of intracellular Salmonella in epithelial cells: replication in the cytosol obscures defects in vacuolar replication.

• DOI: 10.1371/journal.pone.0038732
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Malik-Kale P;Winfree S;Steele-Mortimer O
• 通讯作者: Steele-Mortimer O

Ubiquitination of the bacterial inositol phosphatase, SopB, regulates its biological activity at the plasma membrane.

• DOI: 10.1111/j.1462-5822.2009.01356.x
• 发表时间: 2009-11
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Knodler LA;Winfree S;Drecktrah D;Ireland R;Steele-Mortimer O
• 通讯作者: Steele-Mortimer O

Cytosolic replication in epithelial cells fuels intestinal expansion and chronic fecal shedding of Salmonella Typhimurium.

• DOI: 10.1016/j.chom.2021.04.017
• 发表时间: 2021-07-14
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Chong A;Cooper KG;Kari L;Nilsson OR;Hillman C;Fleming BA;Wang Q;Nair V;Steele-Mortimer O
• 通讯作者: Steele-Mortimer O

Regulatory protein HilD stimulates Salmonella Typhimurium invasiveness by promoting smooth swimming via the methyl-accepting chemotaxis protein McpC.

• DOI: 10.1038/s41467-020-20558-6
• 发表时间: 2021-01-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Cooper KG;Chong A;Kari L;Jeffrey B;Starr T;Martens C;McClurg M;Posada VR;Laughlin RC;Whitfield-Cargile C;Garry Adams L;Bryan LK;Little SV;Krath M;Lawhon SD;Steele-Mortimer O
• 通讯作者: Steele-Mortimer O