Key Points
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Several distinct pattern recognition receptors cooperate during Salmonella-induced bacteraemia to coordinate responses against lipopolysaccharide through canonical and non-canonical pathways.
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Different non-canonical pathways are important for Salmonella-induced gastroenteritis, and this differential activation of innate immune responses results from the differential expression of pattern recognition receptors in epithelial cells and mucosal phagocytes.
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The rapid repression of virulence genes during invasion of the intestinal mucosa enables the causative agent of typhoid fever to evade recognition by pattern recognition receptors.
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The virulence-associated capsular polysaccharide inhibits activation of complement, a pattern recognition receptor that cooperates with Toll-like receptors and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) to orchestrate antibacterial responses.
Abstract
Salmonella enterica serovars are associated with an estimated 1 million deaths annually and are also useful model organisms for investigating the mechanisms of host–bacterium interactions. The insights gained from studies on non-typhoidal Salmonella (NTS) serovars have provided a fascinating overview of the mechanisms by which the innate immune system detects and responds to bacterial pathogens. However, specific virulence factors and changes in virulence gene regulation in S. enterica subsp. enterica serovar Typhi alter the innate immune responses to this pathogen. In this Review, we compare and contrast the interactions of S. Typhi and NTS serovars with host innate immune receptors and discuss why the disease manifestations associated with S. Typhi infection differ considerably from those associated with the closely related NTS serovars.
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Acknowledgements
A.M.K.-G. is supported by the American Heart Association Grant 12SDG12220022. Work in R.M.T.'s laboratory is supported by Public Health Service grants AI050553 and AI090387 from the US National Institutes of Health. Work in A.J.B.'s laboratory is supported by Public Health Service grants AI044170, AI096528 and AI107393.
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Glossary
- Serovars
-
Distinct variants of bacterial species. Each of the more than 2,500 serovars that can be distinguished in the genus Salmonella is defined by an antigen formula, which lists O factors (antigenic epitopes in the O-antigen), H factors (antigenic epitopes in flagellin) and fermentative characteristics.
- Mesenteric lymph nodes
-
Lymph nodes in the mesentery that drain the afferent lymphatic vessels from the small and large intestine.
- Lipopolysaccharide
-
(LPS). Decorates the surface of Salmonella enterica subsp. enterica serovar Typhimurium. A lipid A moiety anchors the LPS molecule in the outer membrane. The lipid A moiety is linked to the oligosaccharide core, which connects to the O-antigen repeat units that extend from the bacterial surface.
- Pattern recognition receptor
-
A protein of the innate immune system that can sense an infection by identifying pathogen-associated molecular patterns or pathogen- associated processes.
- Zoonotic
-
Describes a pathogenic microorganism that spreads from an animal reservoir to cause disease in humans.
- Lipid A
-
A phosphorylated glucosamine disaccharide carrying multiple fatty acid chains that anchor lipopolysaccharide (LPS) in the outer membrane of most Gram-negative bacteria. The lipid A moiety is responsible for the toxicity of LPS, which is also known as endotoxin.
- Pathogen-associated molecular pattern
-
(PAMP). A conserved microbial product that allows the innate immune system to distinguish microorganisms from the host. Although the name implies an association with pathogens, PAMPs are present in all microorganisms, regardless of their pathogenic potential.
- Lipoproteins
-
Proteins that, in Gram-negative bacteria, possess an amino-terminal cysteine residue that is modified with three fatty acids (N-acyl-S-diacylglyceryl cysteine). This triacyl-modified cysteine residue allows lipoproteins to anchor onto bacterial cell membranes.
- CpG dinucleotides
-
Dinucleotides composed of a cytosine triphosphate deoxynucleotide and guanine triphosphate deoxynucleotide. The 'p' refers to the phosphodiester link between the nucleotides. This dinucleotide is often methylated in the DNA of host cells, thereby preventing its recognition by the innate immune system.
- Flagella
-
Proteinaceous surface appendages that function in motility of the bacterial cell. Each flagellum is composed of a globular protein, termed flagellin, which arranges itself into a hollow cylinder to form the flagellar filament.
- Type III secretion system
-
(T3SS). A multiprotein complex found in Gram-negative bacteria that functions in the secretion of proteins, termed effectors, from the bacterial cytosol across three biological membranes into the cytosol of the host cell. T3SS1 and T3SS2 are the two T3SSs present in Salmonella enterica, and are encoded by Salmonella pathogenicity islands (SPIs) SPI-1 and SPI-2, respectively.
- Salmonella pathogenicity island
-
(SPI). A DNA region that encodes virulence factors, and that has a limited phylogenetic distribution owing to its acquisition through horizontal gene transfer. For example, SPI-1 and SPI-2 are present in Salmonella enterica but absent in the closely related species Escherichia coli. SPI-7 is present only in S. enterica subsp. enterica serovars Typhi, Paratyphi C and Dublin.
- O-antigen
-
In Salmonella enterica subsp. enterica serovar Typhimurium, the O-antigen is composed of a trisaccharide backbone, consisting of α-D-mannose–1,4-α-L-rhamnose–1,3-α-D-galactose, and a branching sugar (abequose) that is α-1,3-linked to D-mannose in the backbone. The length of O-antigen chains in S. Typhimurium lipopolysaccharide (LPS) has a trimodal distribution; LPS species can contain short (1–15 repeat units), long (16–35 repeat units) or very long O-antigen chains (more than 100 repeat units).
- Opsonophagocytosis
-
Phagocytosis of a microorganism that is initiated by opsonization to mark it for ingestion. Opsonization involves the binding of an opsonin, such as complement component 3 fragment b (C3b), to the microbial surface.
- Anaphylatoxin
-
A complement component fragment (C3a, C4a or C5a) that is generated during complement activation. Anaphylatoxins have various pro-inflammatory activities and contribute to the generation of septic shock (also known as anaphylactic shock).
- Pyroptosis
-
A form of programmed cell death associated with the generation of pro-inflammatory responses.
- Inflammasome
-
A multiprotein complex involved in the induction of pyroptosis and the proteolytic activation of the cytokines interleukin-1β (IL-1β) and IL-18.
- Antigen-presenting cells
-
(APCs). Cells that display foreign antigens bound to a major histocompatibility complex class II protein on their surface. APCs include dendritic cells, macrophages and B cells.
- Curli amyloid fibrils
-
Functional amyloids that are major proteinaceous components of the extracellular biofilm matrix produced by many Enterobacteriaceae.
- Effector proteins
-
Bacterial proteins that are injected into the host cell cytosol by a type III secretion system.
- Relative bradycardia
-
A heart rate that is considered to be abnormally slow for the individual's current medical condition.
- Capsular polysaccharide
-
A component of a capsule (that is, a polysaccharide layer) that covers the bacterial cell surface. Each polysaccharide chain is attached to the outer membrane of the bacterial cell by a lipid anchor.
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Keestra-Gounder, A., Tsolis, R. & Bäumler, A. Now you see me, now you don't: the interaction of Salmonella with innate immune receptors. Nat Rev Microbiol 13, 206–216 (2015). https://doi.org/10.1038/nrmicro3428
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DOI: https://doi.org/10.1038/nrmicro3428
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