Salmonellae are globally important Gram-negative bacterial pathogens that infect a range of hosts and cause several diseases, including gastroenteritis and typhoid fever. Orally ingested bacteria can survive in the inhospitable environment of the digestive tract and relocate to the intestine, where they invade the intestinal epithelia and either stimulate inflammation and fluid secretion (gastroenteritis) or cross the intestinal barrier and disseminate throughout the reticuloendothelial system (typhoid fever).
Salmonellae use two type III secretion systems (T3SSs) to deliver bacterial virulence proteins, called effectors, directly into host cells. The T3SS that is encoded on Salmonella pathogenicity island (SPI)-1 is responsible for delivering effectors across the plasma membrane and is involved in the invasion of epithelial cells and modulation of inflammation responses. The SPI2-encoded T3SS delivers effectors across the vacuolar membrane and contributes to the survival and replication of intracellular salmonellae. Recent findings suggest that the functions of these two T3SSs are not completely separate and might overlap.
The activities of several SPI1 T3SS effectors stimulate host actin-cytoskeletal rearrangements by either directly modulating actin dynamics or activating host GTPases, which results in membrane ruffling and bacterial uptake. The activation of host GTPases also triggers cell-signalling cascades, which promotes the production of host inflammatory responses.
After bacterial internalization, the host-cell actin cytoskeleton is returned to its normal shape and the inflammatory response is down-modulated. This reversal of actin rearrangement is modulated by SPI1 T3SS effectors, which manipulate the host-cell GTPases and signalling molecules that are involved in inflammation. Intracellular salmonellae resist killing by a range of host innate immune responses and reside in a specialized vacuole, called the Salmonella-containing vacuole (SCV). Sensing of antimicrobial peptides and the low pH of the SCV activates a large number of Salmonella genes that are involved in the remodelling of surface proteins and regulation of virulence genes
The intracellular environment induces expression of the SPI2 T3SS, which is responsible for specific intracellular phenotypes, such as the formation of Salmonella-induced filaments, maintenance of the SCV membrane, perinuclear localization of the SCV and manipulation of the microtubule and actin networks around the SCV.
Salmonellae are important causes of enteric diseases in all vertebrates. Characterization of the molecular mechanisms that underpin the interactions of salmonellae with their animal hosts has advanced greatly over the past decade, mainly through the study of Salmonella enterica serovar Typhimurium in tissue culture and animal models of infection. Knowledge of these bacterial processes and host responses has painted a dynamic and complex picture of the interaction between salmonellae and animal cells. This Review focuses on the molecular mechanisms of these host–pathogen interactions, in terms of their context, significance and future perspectives.
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We would like to thank the entire Salmonella pathogenesis community for its work that made this Review possible. In particular, we are grateful to members of the Miller laboratory, past and present, for their contributions to the ideas that are presented here. We would also like to apologize to those authors whose work was not cited owing to space limitations. A.H. is supported by a Career Development Award from the Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (National Institute of Allergy and Infectious Diseases (NIAID) grant U54 AI057141). M.B.O. is supported by the Comprehensive Training in Inter-Disciplinary Oral Health Research T32 grant DE07132. S.I.M. is supported by the National Institutes of Health, NIAID grants R01 AI30479, R01 AI048683 and U54 AI057141 for the Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research.
A nonspecific process by which small volumes of extracellular fluid are taken up by certain eukaryotic cells owing to the engulfment of fluid in small membrane vesicles.
- Tight junction
The connection between two adjacent cells in a monolayer that is formed by extracellular-matrix and protein complexes; impermeable to water and other molecules.
Used to refer to the endocytosis of large volumes of extracellular fluid and particles by membrane ruffles.
- Reticuloendothelial system
(RES). The meshwork of connective tissue that contains immune cells, such as macrophages, and surrounds tissues that are associated with the immune system, such as the spleen and lymph nodes. Immune cells in the RES provide surveillance of antigens that the body encounters and can be quickly recruited to sites of infection.
- Pathogenicity island
A large region of genomic DNA that encodes genes that are associated with virulence. A pathogenicity island is typically transferred horizontally between bacterial strains and is often inserted into tRNA genes within the genome.
- Transepithelial migration
The movement of cells, such as neutrophils and invading bacteria, from the basolateral (bottom) to the apical (top) surface, or the reverse, of an epithelial cell layer. Migration can also occur between two adjacent cells through tight junctions.
An organism that cannot synthesize certain organic compounds, such as amino acids, that are necessary for its metabolism. For growth, auxotrophic organisms must be able to take up the lacking compound from the surrounding environment.
The post-translational addition of lipid chains, such as farnesyl or geranylgeranyl, to cysteine residues in proteins that contain a prenylation motif called a CaaX box. This process facilitates membrane localization and/or protein–protein interactions.
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Haraga, A., Ohlson, M. & Miller, S. Salmonellae interplay with host cells. Nat Rev Microbiol 6, 53–66 (2008). https://doi.org/10.1038/nrmicro1788
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