Pathogenesis of Salmonella gastroenteritis

INTRODUCTION — Salmonellae cause a broad range of infections, including gastroenteritis, enteric fever, bacteremia, endovascular infections, and focal infections such as osteomyelitis and abscesses [1]. Salmonellae are facultative anaerobic gram-negative bacilli and usually enter the body via the gastrointestinal (GI) tract, where they can persist for long periods of time. Salmonellae can act as both commensals and pathogens and are found in the GI tracts of domestic and wild animals, including insects, reptiles, birds, and mammals.

Although there are many types of Salmonella, they can be divided into two broad categories: those that cause typhoid and enteric fever and those that primarily induce gastroenteritis:

●The typhoidal Salmonella, such as Salmonella Typhi or Salmonella Paratyphi primarily colonize humans, are transmitted via the consumption of fecally contaminated food or water, and cause a systemic illness usually with little or no diarrhea. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)

●The much broader group of nontyphoidal Salmonella usually results from improperly handled food that has been contaminated by animal or human fecal material. It can also be acquired via the fecal-oral route, either from other humans or farm or pet animals [2]. (See "Nontyphoidal Salmonella: Microbiology and epidemiology".)

The bacterial and host factors that contribute to Salmonella gastroenteritis will be reviewed here (figure 1). The approach to patients with Salmonella in a stool culture is discussed separately. (See "Nontyphoidal Salmonella: Gastrointestinal infection and asymptomatic carriage".)

GENERAL ISSUES — A number of different serovars of Salmonella cause human infection. The source of infection typically is from food. For every laboratory-confirmed case of Salmonella, there are many other undetected cases; one estimate is 29 infections for every 1 culture-confirmed case [3].

Serotypes — The 2000-plus serovars of Salmonella can be characterized by three major antigens: the somatic O antigen, which is derived from the LPS cell wall component; the flagellar H antigen, and the surface Vi antigen. The O-antigen is widely used by clinical laboratories to divide Salmonella into serogroups A, B, C1, C2, D, and E (table 1). Significant cross-reactivity can occur between serogroups. The serogroups cannot be used to divide enteric fever-causing strains from gastroenteritis-causing strains: group D contains both Salmonella enteritidis and S. Typhi, while group B contains Salmonella Typhimurium as well as some strains of S. Paratyphi. To investigate a possible outbreak, further identification must be done with bacteriophage typing, restriction fragment length polymorphism analysis, pulsed-field gel electrophoresis, and plasmid profile determination.

The host specificity of different Salmonella serotypes often determines the nature of the clinical illness. Classic typhoid or enteric fever is caused by S. Typhi and S. Paratyphi. These strains are highly adapted for humans and do not colonize or cause disease in animals, though S. Paratyphi has very rarely been associated with domestic animals (see "Pathogenesis of enteric (typhoid and paratyphoid) fever"). Those serotypes which cause enteric fever are frequently not associated with significant diarrheal symptoms, although enteric fever may be heralded by transient diarrhea prior to the onset of fever.

S. enteritidis and S. Typhimurium have broad host ranges and may produce colonization or gastroenteritis in humans, mice, and fowl (see "Nontyphoidal Salmonella: Microbiology and epidemiology"). These serotypes are most frequently associated with gastroenteritis in humans because of the large reservoirs of bacteria in domestic animals. Salmonella choleraesuis (adapted for swine) and Salmonella dublin (adapted for cattle) are associated with human septicemia and metastatic foci of infection but are uncommon causes of gastroenteritis [4]. Salmonella gallinarum-pullorum (adapted for fowl) causes relatively transient illness in humans only after very large inocula are ingested. The molecular bases of these species specificities is complex and currently under investigation.

The epidemiology of Salmonella has evolved over time. A detailed atlas of Salmonella infections from 1968 to 2011 in the United States is available through the Centers for Disease Control and Prevention (CDC) [5]. During the 2000s, the incidence of S. Typhimurium decreased, while serotypes Newport, Mississippi, and Javiana increased in incidence. Specific control programs focusing on contaminated eggs might have led to the reduction of S. enteritidis infections. Rates of antibiotic resistance among several serotypes have been increasing and are an area of significant concern; a substantial proportion of S. Typhimurium and Salmonella newport isolates are multidrug resistant [6]. In the United States, an estimated 6200 culture-confirmed Salmonella infections with clinically important resistance occurred annually from 2004 to 2012 [7]. Most cases of human salmonellosis are almost entirely limited to the serotypes of subspecies Salmonella enterica, with the top five serotypes responsible for human disease being S. Enteritidis, S. Typhimurium, S. Infantis, S. Stanley, and S. Newport; most human infections due to non-enterica subspecies develop in adults with weakened immune systems [8].

Sources of infection — There are an estimated two to four million cases of Salmonellosis per year in the United States, with gastroenteritis as the most common clinical presentation. Nontyphoidal Salmonella account for 9.7 percent of all bacterial foodborne illnesses and 30.6 percent of deaths as of 1999 [9]; between the time periods 1996 to 1998 and 2005, the number of Salmonella cases decreased by 9 percent [10]. Salmonella gastroenteritis usually results from improperly handled food. It can also be acquired via the fecal-oral route, either from other humans or farm or pet animals. Sources of infection are discussed in detail elsewhere. (See "Nontyphoidal Salmonella: Microbiology and epidemiology", section on 'Modes of transmission'.)

Infectious dose — Data on the number of Salmonella organisms required for clinical illness have been obtained from studies on human volunteers and outbreaks in which the vehicle of inoculation was quantitatively cultured [11]. Several general statements about infectious doses can be made:

●Large inocula (>10⁴) produce higher rates of illness after shorter incubation periods than small inocula (≤10³).

●Asymptomatic excretion may occur after ingestion of small inocula, although even very small inocula (5 to 100 organisms) may cause disease in susceptible hosts.

●Antibiotic use can reduce the infectious dose necessary to cause disease by diminishing the normally protective indigenous flora (see below).

●The infectious dose is lower in patients with clinical conditions associated with a reduction in gastric acidity such as neonates [12], achlorhydric states [13], gastric surgery [14,15], and the use of antacids or H2 blockers [15,16].

●Water supplies are contaminated at lower levels than food, resulting in lower attack rates and longer incubation periods in waterborne outbreaks.

●Salmonella may persist for months in cheese, frozen meat, or ice cream.

PATHOGENESIS — A number of factors related both to the pathogen and the host influence the pathogenesis of Salmonella gastroenteritis.

Interaction of Salmonellae with enteric host defenses — Ingested microorganisms must traverse the acidic barrier of the stomach in order to establish enteric infection (table 2). Although Salmonella and other enteric pathogens survive poorly at the very low pH encountered in the stomach, Salmonella exhibit increased tolerance to "acid shock" if first exposed to a moderately acidic environment (pH 4 to 5). The organism's ability to adapt to low pH has been called the acid tolerance response [17].

Salmonellae that survive passage through the stomach must then compete with the normal intestinal microbial flora. The indigenous flora is an important but often overlooked barrier to infection with enteric pathogens. Elegant mouse studies performed in the 1960s showed that a single injection of streptomycin reduced the oral infectious dose of S. Typhimurium by over 100,000-fold [18]. Studies in animals have shown that the protective effect of indigenous microbes is due to a variety of factors including competition for nutrients, maintenance of a low luminal pH, and production of inhibitory compounds such as volatile fatty acids [19,20].

These findings appear to be applicable to humans, as can be illustrated by the following observations:

●Prophylactic antimicrobial therapy increases the frequency of salmonellosis among travelers [21].

●Patients found to be infected during an outbreak of multidrug-resistant S. Typhimurium enteritis used antimicrobials in the month before the onset of illness much more frequently than controls (30 versus 6 percent) [22]. A similar association with prior antimicrobial use was noted in a multistate outbreak of illness caused by Salmonella havana which was pansensitive to antimicrobial agents (30 versus 13 percent) [23]. The association persisted even when controlled for the presence of underlying illness or immunosuppression.

S. Typhimurium has a marked and unique growth advantage over other bacteria when using a specific nutrient, ethanolamine, which is released from host tissue in the lumen of the inflamed intestine and is not utilizable by competing bacteria [24]. Thus, by inducing intestinal inflammation, S. Typhimurium sidesteps nutritional competition and creates a significant survival advantage for itself.

In addition to competition from the indigenous bacterial flora, Salmonella must withstand a gamut of enteric defenses including bile salts, pancreatic enzymes, Paneth cell antimicrobial peptides [25], and secretory IgA [26].

The stringent response (SR) system, mediated by guanosine pentaphosphate ([p]ppGpp), has been implicated in the regulation of invasion, virulence, persistence, and latency of several bacterial pathogens and intracellular obligate parasites; similar S. Typhi mutants show severely impaired virulence-associated traits, such as motility, chemotaxis, and Vi antigenic capsule formation, leading to markedly attenuated adhesion, invasion of the intestinal epithelial cells, and intracellular survival within macrophages [27].

Mechanisms of adherence and invasion — There are two main components to Salmonella infection of the GI tract: adherence and subsequent invasion. Adherence is complex and is mediated by multiple genes. Fimbriae are very important in adhering to and adapting to a eukaryotic cell surface [28]; several fimbrial operons may facilitate adherence [29]. Biofilms may play a role as well [28]. The invasion operon (inv) can also induce adherence [30].

Invasion may be achieved by several different mechanisms:

●Salmonella can selectively attach to specialized epithelial cells overlying Peyer's patches in the colon known as M (microfold) cells. These cells are an important portal of entry of Salmonellae and other pathogens into the submucosal lymphoid system [31]. M cells are highly endocytic and can rapidly transfer material from their luminal side to their basal side, where the T cells and antigen-presenting cells reside, ready to elicit an immune response.

●It has been suggested that the cells of the columnar epithelium may also be an important common portal of entry for Salmonella, particularly since they greatly outnumber the M cells [32].

●Salmonellae can also induce nonphagocytic cells such as enterocytes to internalize them. This process of bacterial-mediated endocytosis has been extensively studied in vitro and appears to be important in the pathogenesis of Salmonella gastroenteritis [33,34].

●Invasion can also occur via the dendritic cells that intercalate between epithelial cells by extending protrusions into the gut lumen.

●Numerous small foci of solitary intestinal lymphoid tissues (SILTs) with a strong inflammatory response can be found in the murine small intestine; Salmonella can be observed within these SILTs at early stages of infection, and the SILTs may act as portals of entry [35].

Following invasion into the cell, the bacteria remain within a modified phagosome known as the Salmonella-containing vacuole (SCV), within which they will survive and replicate. Type III secretion systems are used to translocate bacterial effector proteins into the host cell, mediating both invasion and vacuole biogenesis. Vacuole biogenesis is a complex and dynamic process involving extensive membrane remodeling, interactions with the endolysosomal pathway, actin rearrangements, and microtubule-based movement and tubule extension [36]. Interferon 1-mediated signaling and control of lysosomal function appear to modulate intestinal epithelial cell death and systemic spread of Salmonella [37].

The mechanisms of persistent Salmonella fecal shedding of Salmonella are under investigation. The shdA gene, which encodes an outer membrane autotransporter protein that binds fibronectin, is required for persistent shedding of S. Typhimurium in mice [38]. This raises the question of whether this locus might mediate adherence of Salmonella at other clinically important structures known to be foci of metastatic infection, such as arteries and bone.

Pathogenicity islands — Two Salmonella "pathogenicity islands" (SPI) have been found, termed SPI-1 and 2, each about 40 kilobases of DNA and located at centrosomes 63 and 30 of the chromosome, respectively [39-44]. Both SPIs encode multiple virulence factors, including Type III secretions systems (TTSS). The TTSS creates a hypodermic needle-like apparatus (figure 2) and injects proteins into the cells, facilitating uptake of the bacteria into those cells. SPI-1 encodes genes needed for nonphagocytic cell invasion via a ruffling mechanism and initiation of intestinal secretory and inflammatory responses. SPI-2 is induced within the cell and contains genes needed for survival and replication within macrophages [45]. Some of these genes induce secretory and inflammatory responses [46,47]. Some of these genes on SPI-1 encode proteins homologous to Shigella proteins which direct the export and translocation of signaling molecules capable of interacting with eukaryotic cells [39,40]. The secreted proteins of both Salmonella and Shigella induce ruffled projections in eukaryotic cell membranes which subsequently invaginate and internalize the invading bacterium within a membrane bound vacuole, called macropinocytosis [48].

These TTSSs facilitate bacterial entry, replication within cells, and target cell transcriptional reprogramming via effector proteins that, although highly conserved across different serovars, have enough differences to explain variations in clinical presentations. Analyzing transcriptional responses of cultured epithelial cells infected with S. Typhi and S. Typhimurium, studies have found serovar-specific transcriptional fingerprints that correlated with activation of specific signal transduction pathways and effector proteins, which may help explain the variations in the pathogenic mechanisms and clinical illnesses [49].

Mutants lacking these genes display reduced virulence. In one study avirulent environmental isolates of Salmonella senftenberg and Salmonella litchfield contained deletions in SPI-1, while clinical isolates of the same serotypes retained the gene cluster [50].

Inflammatory response mechanisms — In addition to facilitating their own uptake, virulent strains of Salmonella are able to induce migration of subepithelial neutrophils across polarized epithelial cells in vitro [51]. A substantial neutrophil infiltration into the intestine occurs in S. Typhimurium-induced colitis in humans; whether this is due to effectors from Salmonella or innate pathways of inflammation triggered by pathogen recognition receptors on cells in the lamina propria is a matter of debate [52]. The paracellular traffic of neutrophils has been hypothesized to induce diarrhea by causing paracellular fluid and electrolyte fluxes. This theory is supported by the observation that strains which do not usually cause enteritis, such as S. Typhi and S. gallinarum, also do not induce neutrophil transmigration [53].

In addition to IL-8, Salmonella induce other proinflammatory cytokines such as GM-CSF, monocyte chemotactic protein-1, and tumor necrosis factor-alpha in colonic epithelial cells, which in turn mediate further immune responses [54]. Macrophages respond to S. Typhimurium infection via flagellin-mediated activation of Ipaf, a NACHT-leucine-rich repeat family member that activates caspase-1 [55]. Activated caspase-1 is required for the secretion of proinflammatory cytokines, such as interleukin (IL)-1beta and IL-18, and is important in host defense against a variety of pathogens; caspase-1-deficient mice are more susceptible to several pathogens including, Shigella, Listeria, and Francisella tularensis [56-58], as well as Salmonella [59].

Lipid A is the biologically active component of lipopolysaccharide (LPS) found in the cell wall of Salmonella and other gram-negative bacteria. Lipid A is toxic to mammalian cells and is a potent immunomodulator. Certain features of the lipid A in Salmonella may correlate with virulence or with activation of host inflammation [60,61]. Lipid A induces toll-like receptor 4 (TLR4)-mediated responses, which are important for host defense against Salmonella infection, and modifications in lipid A as part of Salmonella's adaptation to host environments reduce this signaling [62]. Death in mice from Salmonella may be related to the toxic effect of lipid A, which triggers further production of TNF-alpha and IL-1 beta. S. Typhimurium mutants with a defective lipid A molecule have greatly attenuated virulence in mice [63]. Structural modifications of lipid A are influenced by the Salmonella virulence regulatory locus (phoP/phoQ) which responds to a variety of host intracellular environmental signals [64]. For example, antimicrobial peptides have been shown to be part of the first step in signal transduction across the bacterial membrane, resulting in activation of phoQ and promotion of bacterial virulence [65]. PhoP has also been found to bind a promoter region of a drug efflux system, thus connecting virulence with possible drug resistance [66].

Enterotoxins may also play a role in Salmonella gastroenteritis. An enterotoxin, encoded by the stn gene and antigenically similar to cholera toxin has been identified [67-69]. While many Salmonellae carry the stn gene, only a fraction express the gene, as assessed by CHO cell assay [70]. While the tropism of typhoid toxin to immune cells likely alters innate and adaptive immune responses in Salmonella Typhi pathogenesis, the non-typhoid ortholog Javiana toxin does not cause the same toxicity despite the high degree of amino acid sequence similarity between these proteins. They have markedly different glycan-binding preferences and virulence [71]. Vaccination with S. Javiana or its toxin results in cross-reactive protection against lethal-dose typhoid toxin challenge in mice, which may help advance vaccine development.

Additional characterization of the enterotoxin is needed to assess its role in human pathogenesis.

Survival within phagocytes — Salmonellae have long been known to persist within the reticuloendothelial system. Macrophages may be the main cell type to support bacterial growth in vivo, and this growth is regulated by both the host and the Salmonella [72]. The ability of Salmonella to survive within macrophages contributes to the dissemination of the microorganism from the submucosa to the circulation and the reticuloendothelial system. Intracellular bacterial growth within phagocytes is limited by mechanisms requiring reactive oxygen intermediates, magnesium transporters [73], reactive nitrogen intermediates, lysosomal enzymes, and defensins. Itaconate, an antimicrobial metabolite produced within mitochondria also contributes [74]. S. Typhimurium has been shown to induce succinate accumulation [75], which fuels its own virulence by promoting resistance of antimicrobials and type III secretion of virulence factors. Both the phoP/phoQ virulence regulatory locus [76-78] and the SPI-2 contain genes that are important for survival within macrophages. The importance of this process is illustrated by studies that showed that phoP/phoQ-deleted S. Typhimurium, when used as a vaccine vector, caused no bacteremia or late sequelae in a limited number of subjects who received a large oral inoculum [79]. Isolates of S. Typhimurium that are unable to survive within macrophages in vitro are avirulent in mice [80].

Role of virulence plasmids — Nontyphoidal Salmonellae also carry a variety of virulence plasmids [81]. A highly conserved 8 kilobase region of DNA contained within these plasmids has been associated with the ability of strains to induce bacteremia and persist within the reticuloendothelial system [81,82]. S. Typhimurium has a self-transmissible [83] 90 kilobase virulence plasmid that contains the genes spvRABCD and while it increases the growth rate of Salmonellae in macrophages, it may have a limited contribution to virulence [84]. The virulence plasmid stimulates IL-12 production in a mouse model, which may lead to attenuated T cell proliferation [85].

Immune response to Salmonella infection — Because of the frequency and nonspecific nature of the symptoms of Salmonella gastroenteritis, little is known about the rates of reinfection and correlates of immunity. The innate immune system, cell-mediated immunity, and humoral immunity all play important roles in limiting Salmonella infection.

Innate immune system — The innate immune system plays a critical role in the initial response to Salmonella infection. It may be the determining factor in whether the infection is subclinical or more aggressive. The importance of macrophages and polymorphonuclear (PMN) leukocyte response to Salmonella has been well described. Neutropenic mice have a high mortality in experimental Salmonella infection [86], and depressed PMN function increases the incidence of Salmonella infection in humans. These conditions most commonly include sickle cell anemia [87], malaria [88,89], schistosomiasis [90], and histoplasmosis [91]. In addition, Toll receptor agonists such as LPS, lipoprotein, and flagellin stimulate proinflammatory cytokine production, resulting in TNF-alpha and interleukin responses [32]. Activation of Toll-like receptor 5 and Ipaf by Salmonella flagellin has been a significant finding [92].

Cell-mediated immunity — Cell-mediated immunity plays an important role in clearing infection and protecting against subsequent Salmonella infection. Clinical vigilance in the diagnosis and management of Salmonella infections should be increased in settings associated with cellular immunosuppression. As an example, infection is more severe and prolonged in patients with depressed cellular immunity due to glucocorticoids [93], AIDS [94-96], and malignancy [97]. In one study, nontyphoidal Salmonella (14 percent) were the second most frequent bacterial isolate after Staphylococcus aureus (29 percent) in a study of 249 bacteremias in HIV-infected individuals [98]. Nude mice and mice deficient in alpha-beta T cells are more susceptible to Salmonella infections. Murine models suggest that CD4+ T cells are more contributory than CD8+ T cells [32].

Humoral immune responses — The humoral response to Salmonella infection is complex and may be protective or maladaptive. Its importance in containing Salmonella infection is illustrated by the protective immunity induced in vaccination studies with S. Typhi. Mice deficient in B cells due to a targeted deletion of the Ig-mu gene show increased susceptibility to Salmonella infection and are unable to mount a significant convalescent immune response [99]. In addition, mucosal humoral immune responses may play a contributory role. Murine studies have shown that secretion of large amounts of a single monoclonal IgA directed against S. Typhimurium lipopolysaccharide (LPS) into the intestinal lumen provides significant protection against systemic disease [40]. Furthermore, mucosal antibodies to nontyphoidal Salmonellae appear to inhibit the "take" of the oral live attenuated typhoid fever vaccine Ty21a [100].

However, in a study that evaluated the effect of serum from HIV-infected patients on the killing of S. Typhimurium in vitro, a high serum concentration of antibodies against the LPS of non-typhoidal Salmonellae paradoxically prevented the destruction of Salmonella [101]. The authors postulated that inhibitory antibodies in the serum of HIV-infected individuals could be responsible for this effect by blocking the action of bactericidal antibodies. These results suggest that the preferred vaccine target should be the bacterial outer-membrane proteins of non-typhoidal Salmonellae as opposed to LPS, since LPS could potentially elicit inhibitory rather than the desired bactericidal antibodies.

Interaction with intestinal flora — Both pathogen transmission and pathogen clearance from the gut lumen can be mediated by the microbiota. In one study, mice with low complexity gut flora failed to clear S. Typhimurium from the gut lumen, and pathogen clearance was achieved by transferring a normal complex microbiota [102]. The normal microbiota were able to grow from low numbers in abnormal conditions and gradually clear even very high pathogen loads from the gut lumen, a site inaccessible to most "classical" immune effector mechanisms. Thus, besides preventing pathogen transmission by an intact microbiota (also known as colonization resistance), the microbiota also facilitates pathogen clearance, a second, novel protective function. More recent work suggests this may be mediated by microbiota-enhanced antibacterial interferon-gamma responses [103], which can be augmented by transfer of specific commensal communities. Increasingly, other specific mechanisms are being elucidated. For example, Enterococcus faecium's secreted antigen A (SagA) is sufficient to protect Caenorhabditis elegans against Salmonella and other pathogens. SagA's peptidoglycan hydrolase activity generates muramyl-peptide fragments that enhance epithelial barrier integrity.

In a trial of the oral live-attenuated typhoid vaccine Ty21a, bacterial 16S rRNA pyrosequencing was employed to evaluate whether oral immunization resulted in alterations of the microbiota and whether a given microbiota composition is associated with defined S. Typhi-specific immunological responses [104]. No discernible perturbations of the bacterial assemblage were found after vaccine administration. Among individuals able to mount a positive humoral response, no differences in microbial composition, diversity, or temporal stability were observed; however, individuals displaying broader (multiphasic) cell mediated immune responses harbored more diverse, complex communities. Further studies of the immune-modulatory properties of the human microbiota and the impact on disease transmission, pathogen clearance, and the response to vaccination is warranted.

Persisters — Some non-replicating Salmonella display a reversible, antibiotic-tolerant phenotype and can persist following antibiotic treatment and then revert to growth phase. This is of particular importance for S. Typhi, which has a chronic phase. Research on Salmonella growth and survival during antibiotic treatment has shown that antibiotic killing correlated with single-cell division rates, such that non-dividing Salmonella had the highest survival rates but were rare [105]. Most surviving bacteria were from the more common moderately growing, partially tolerant Salmonella. Using fluorescent single-cell analysis, other studies have shown that Salmonella persisters were part of a nonreplicating population that formed immediately after uptake by macrophages and were induced by vacuolar acidification and nutritional deprivation, similar to conditions that induce Salmonella virulence gene expression [106]. After phagocytosis by naïve macrophages, some persisters were subsequently able to resume intracellular growth, which could be a reservoir for relapsing infection. In response to the gallbladder environment, Salmonella can undergo genetic changes resulting in hyper-biofilm isolates with improved persistence, especially in the presence of gallstones, albeit at the cost of decreased virulence [107].

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SUMMARY

●The 2000-plus serovars of Salmonella can be characterized by three major antigens: the somatic O antigen, which is derived from the lipopolysaccharide cell wall component, the flagellar H antigen, and the surface Vi antigen. (See 'Serotypes' above.)

●The size of the inoculum is proportional to the frequency and rapidity of disease onset, but even small inocula can cause disease. Enteric host factors that defend against Salmonella infection include the acidic environment of the stomach and the normal intestinal microbial flora. The infectious dose necessary to cause disease can be lower in settings of antibiotic use and reduction of gastric acid. (See 'Infectious dose' above and 'Interaction of Salmonellae with enteric host defenses' above.)

●Salmonellae adhere to and invade the gastrointestinal tract and submucosal lymphoid system through several different mechanisms. Bacterial entry into and survival within host cells are facilitated by multiple virulence factors. (See 'Mechanisms of adherence and invasion' above and 'Pathogenicity islands' above.)

●The ability of Salmonella to survive within macrophages contributes to the dissemination of the microorganism from the submucosa to the circulation and the reticuloendothelial system. (See 'Survival within phagocytes' above.)

●Virulent strains of Salmonella induce multiple host inflammatory responses and cytokines. This is in part mediated by lipid A, a component of lipopolysaccharide in the cell wall. (See 'Inflammatory response mechanisms' above.)

●The host innate immune response may determine whether Salmonella infection is subclinical or more aggressive. Adaptive cell-mediated immunity plays an important role in clearing and protecting against subsequent infection. The humoral response is complex and may be protective or maladaptive. (See 'Immune response to Salmonella infection' above.)

●An intact host intestinal flora, or microbiome, plays a role in preventing infection through the gastrointestinal route and also facilitates pathogen clearance. (See 'Interaction with intestinal flora' above.)