Bacteria of the genus Salmonella are highly adapted for growth in both humans and animals and cause a wide spectrum of disease. The growth of serotypes S. typhi and S. paratyphi is restricted to human hosts, in whom these organisms cause enteric (typhoid) fever. The remaining serotypes (nontyphoidal Salmonella, or NTS) can colonize the gastrointestinal tracts of a broad range of animals, including mammals, reptiles, birds, and insects. More than 200 serotypes are pathogenic to humans, in whom they often cause gastroenteritis and can be associated with localized infections and/or bacteremia.
This large genus of gram-negative bacilli within the family Enterobacteriaceae consists of two species: S. enterica, which contains six subspecies, and S. bongori. S. enterica subspecies I includes almost all the serotypes pathogenic for humans. According to the current Salmonella nomenclature system, the full taxonomic designation S. enterica subspecies enterica serotype typhimurium can be shortened to Salmonella serotype typhimurium or simply S. typhimurium.
Members of the seven Salmonella subspecies are classified into >2500 serotypes (serovars) according to the somatic O antigen [lipopolysaccharide (LPS) cell-wall components], the surface Vi antigen (restricted to S. typhi and S. paratyphi C), and the flagellar H antigen. For simplicity, most Salmonella serotypes are named for the city where they were identified, and the serotype is often used as the species designation.
Salmonellae are gram-negative, non-spore-forming, facultatively anaerobic bacilli that measure 2–3 by 0.4–0.6 μm. The initial identification of salmonellae in the clinical microbiology laboratory is based on growth characteristics. Salmonellae, like other Enterobacteriaceae, produce acid on glucose fermentation, reduce nitrates, and do not produce cytochrome oxidase. In addition, all salmonellae except S. gallinarum-pullorum are motile by means of peritrichous flagella, and all but S. typhi produce gas (H2S) on sugar fermentation. Notably, only 1% of clinical isolates ferment lactose; a high level of suspicion must be maintained to detect these rare clinical lactose-fermenting isolates.
Although serotyping of all surface antigens can be used for formal identification, most laboratories perform a few simple agglutination reactions that define specific O-antigen serogroups, designated A, B, C1, C2, D, and E. Strains in these six serogroups cause ∼99% of Salmonella infections in humans and other warm-blooded animals. Molecular typing methods, including pulsed-field gel electrophoresis and polymerase chain reaction (PCR) fingerprinting, are used in epidemiologic investigations to differentiate Salmonella strains of a common serotype.
All Salmonella infections begin with ingestion of organisms, most commonly in contaminated food or water. The infectious dose is 103–106 colony-forming units. Conditions that decrease either stomach acidity (an age of <1 year, antacid ingestion, or achlorhydric disease) or intestinal integrity (inflammatory bowel disease, prior gastrointestinal surgery, or alteration of the intestinal flora by antibiotic administration) increase susceptibility to Salmonella infection.
Once S. typhi and S. paratyphi reach the small intestine, they penetrate the mucus layer of the gut and traverse the intestinal layer through phagocytic microfold (M) cells that reside within Peyer's patches. Salmonellae can trigger the formation of membrane ruffles in normally nonphagocytic epithelial cells. These ruffles reach out and enclose adherent bacteria within large vesicles by a process referred to as bacteria-mediated endocytosis (BME). BME is dependent on the direct delivery of Salmonella proteins into the cytoplasm of epithelial cells by a specialized bacterial secretion system (type III secretion). These bacterial proteins mediate alterations in the actin cytoskeleton that are required for Salmonella uptake.
After crossing the epithelial layer of the small intestine, S. typhi and S. paratyphi, which cause enteric (typhoid) fever, are phagocytosed by macrophages. These salmonellae survive the antimicrobial environment of the macrophage by sensing environmental signals that trigger alterations in regulatory systems of the phagocytosed bacteria. For example, PhoP/PhoQ (the best-characterized regulatory system) triggers the expression of outer-membrane proteins and mediates modifications in LPS so that the altered bacterial surface can resist microbicidal activities and potentially alter host cell signaling. In addition, salmonellae encode a second type III secretion system that directly delivers bacterial proteins across the phagosome membrane into the macrophage cytoplasm. This secretion system functions to remodel the Salmonella-containing vacuole, promoting bacterial survival and replication.
Once phagocytosed, typhoidal salmonellae disseminate throughout the body in macrophages via the lymphatics and colonize reticuloendothelial tissues (liver, spleen, lymph nodes, and bone marrow). Patients have relatively few or no signs and symptoms during this initial incubation stage. Signs and symptoms, including fever and abdominal pain, probably result from secretion of cytokines by macrophages and epithelial cells in response to bacterial products that are recognized by innate immune receptors when a critical number of organisms have replicated. Over time, the development of hepatosplenomegaly is likely to be related to the recruitment of mononuclear cells and the development of a specific acquired cell-mediated immune response to S. typhi colonization. The recruitment of additional mononuclear cells and lymphocytes to Peyer's patches during the several weeks after initial colonization/infection can result in marked enlargement and necrosis of the Peyer's patches, which may be mediated by bacterial products that promote cell death as well as the inflammatory response.
In contrast to enteric fever, which is characterized by an infiltration of mononuclear cells into the small-bowel mucosa, NTS gastroenteritis is characterized by massive polymorphonuclear leukocyte (PMN) infiltration into both the large- and small-bowel mucosa. This response appears to depend on the induction of interleukin (IL) 8, a strong neutrophil chemotactic factor, which is secreted by intestinal cells as a result of Salmonella colonization and translocation of bacterial proteins into host cell cytoplasm. The degranulation and release of toxic substances by neutrophils may result in damage to the intestinal mucosa, causing the inflammatory diarrhea observed with nontyphoidal gastroenteritis.
Enteric (typhoid) fever is a systemic disease characterized by fever and abdominal pain and caused by dissemination of S. typhi or S. paratyphi. The disease was initially called typhoid fever because of its clinical similarity to typhus. However, in the early 1800s, typhoid fever was clearly ...