title: The Salmonella SPI2 effector SseI mediates long-term systemic infection by modulating host cell migration.
abstract: 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.
authors: Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, California, United States of America.
authors: Laura M
authors: LM
authors: McLaughlin
authors: Gregory R
authors: GR
authors: Govoni
authors: Christiane
authors: C
authors: Gerke
authors: Smita
authors: S
authors: Gopinath
authors: Kaitian
authors: K
authors: Peng
authors: Grace
authors: G
authors: Laidlaw
authors: Yueh-Hsiu
authors: YH
authors: Chien
authors: Ha-Won
authors: HW
authors: Jeong
authors: Zhigang
authors: Z
authors: Li
authors: Matthew D
authors: MD
authors: Brown
authors: David B
authors: DB
authors: Sacks
authors: Denise
authors: D
authors: Monack
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D002465:Cell Movement; D003713:Dendritic Cells / Q000382:microbiology / Q000502:physiology; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000382:microbiology / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D012480:Salmonella Infections / Q000209:etiology*; D019779:Salmonella enterica / Q000472:pathogenicity*; D013154:Spleen / Q000276:immunology; D013997:Time Factors
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella