Etiology

Salmonellae are motile, nonsporulating, nonencapsulated, gram-negative rods that grow aerobically and are capable of facultative anaerobic growth. They are resistant to many physical agents but can be killed by heating to 130°F (54.4°C) for 1 hr or 140°F (60°C) for 15 min. They remain viable at ambient or reduced temperatures for days and may survive for weeks in sewage, dried foodstuffs, pharmaceutical agents, and fecal material. Like other members of the family Enterobacteriaceae, Salmonella possesses somatic O antigens and flagellar H antigens.

With the exception of a few serotypes that affect only 1 or a few animal species, such as Salmonella dublin in cattle and S. choleraesuis in pigs, most serotypes have a broad host spectrum. Typically, such strains cause gastroenteritis that is often uncomplicated and does not need treatment but can be severe in the young, the elderly, and patients with weakened immunity. The causes are typically Salmonella Enteritidis (Salmonella enterica serotype Enteritidis) and Salmonella Typhimurium (S. enterica serotype Typhimurium), the 2 most important serotypes for salmonellosis transmitted from animals to humans. Nontyphoidal salmonellae have emerged as a major cause of bacteremia in Africa, especially among populations with high incidence of HIV infection.

Epidemiology

Salmonellosis constitutes a major public health burden and represents a significant cost to society in many countries. It is estimated that in the USA alone an estimated 1.4 million nontyphoidal Salmonella infections occurred in 2007, with an estimated $2.5 billion cost due to lost productivity and medical treatment. Although there is little information on the epidemiology and the burden of Salmonella gastroenteritis from developing countries, Salmonella infections are recognized as major causes of childhood diarrheal illness. With the growing burden of HIV infections and malnutrition in Africa, nontyphoidal Salmonella bacteremic infections have emerged as a major cause of morbidity and mortality among children and adults.

Nontyphoidal Salmonella infections have a worldwide distribution, with an incidence proportional to the standards of hygiene, sanitation, availability of safe water, and food preparation practices. In the developed world, the incidence of Salmonella infections and outbreaks has increased several-fold over the past few decades, which may be related to modern practices of mass food production that increase the potential for epidemics. Salmonella gastroenteritis accounts for over half of all episodes of bacterial diarrhea in the USA, with incidence peaks at the extremes of ages, among young infants and the elderly. Most human infections have been caused by S. Enteritidis; the prevalence of this organism has decreased over the past decade, with S. Typhimurium overtaking it in some countries.

The rise in Salmonella infections in many parts of the world over the past 3 decades may also be related to intensive animal husbandry practices, which selectively promote the rise of certain strains, especially drug-resistant varieties that emerge in response to the use of antimicrobials in food animals. Poultry products were traditionally regarded as a common source of salmonellosis, but consumption of a range of foods has now been associated with outbreaks, including fruits and vegetables. Although this change in epidemiology may be related to selective pressure from the use of antimicrobials, there may be other factors, such as the rise of strains with a selective propensity to develop resistance and virulence. It appears that multidrug-resistant strains of Salmonella are more virulent than susceptible strains and that poorer outcome does not simply relate to the delay in treatment response due to empirical choice of an ineffective antibiotic. Strains of multidrug-resistant Salmonella such as S. Typhimurium phage type DT104 harbor a genomic island that contains many of the drug resistance genes. It is possible that these integrons also contain genes that express virulence factors. The global spread of multidrug-resistant S. Typhimurium phage type DT104 in animals and humans may be related to the growing use of antimicrobials and may be facilitated by international and national trade of infected animals.

Several risk factors are associated with outbreaks of Salmonella infections. Animals constitute the principal source of human nontyphoidal Salmonella disease, and cases have occurred in which individuals have had contact with infected animals, including domestic animals such as cats, dogs, reptiles, pet rodents, and amphibians. Specific serotypes may be associated with particular animal hosts; children with S. enterica serovar Marina typically have exposure to pet lizards. In 1996 more than 50,000 cases of salmonellosis related to domestic lizards were reported to the U.S. Centers for Disease Control and Prevention (CDC). Domestic animals probably acquire the infection in the same way that humans do, through consumption of contaminated raw meat, poultry, or poultry-derived products. Animal feeds containing fishmeal or bone meal contaminated with Salmonella are an important source of infection for animals. Moreover, subtherapeutic concentrations of antibiotics are often added to animal feed to promote growth. Such practices promote the emergence of antibiotic-resistant bacteria, including Salmonella, in the gut flora of the animals, with subsequent contamination of their meat. There is strong evidence to link resistance of S. Typhimurium to fluoroquinolones with the use of this group of antimicrobials in animal feeds. Animal-to-animal transmission can occur, but most infected animals are asymptomatic.

An increasing number of produce-associated foodborne outbreaks in the USA associated with bacterial contamination are primarily from Salmonella. Although almost 80% of Salmonella infections are discrete, outbreaks can pose an inordinate burden on public health systems. In an evaluation of 604 outbreaks of foodborne disease in schools in the USA, Salmonella was the most commonly identified pathogen, accounting for 36% of outbreak reports with a known etiology. Salmonella infections in chickens increase the risk for contamination of eggs, and both poultry and eggs have been regarded as a dominant cause of common-source outbreaks. However, a growing proportion of Salmonella outbreaks are also associated with other food sources. The CDC reports that between 2002 and 2003, 31 food produce–associated Salmonella outbreaks were reported, compared with only 29 poultry-related outbreaks. The food sources included many fruits and vegetables, such as tomatoes, sprouts, watermelon, cantaloupe, lettuce, and mangoes.

In addition to the effect of antibiotic use in animal feeds, the relationship of Salmonella infections to prior antibiotic use among children in the previous month is well recognized. This increased risk for infection in people who have received antibiotics for an unrelated reason may be related to alterations in gut microbial ecology, which predispose them to colonization and infection with antibiotic-resistant Salmonella isolates. These resistant strains of Salmonella are also more virulent. It is estimated that antimicrobial resistance in Salmonella may result in about 30,000 additional Salmonella infections annually, leading to about 300 hospitalizations and 10 deaths.

Given the ubiquitous nature of the organism, nosocomial infections with nontyphoidal Salmonella strains can also occur through contaminated equipment and diagnostic or pharmacologic preparations, particularly those of animal origin (pancreatic extracts, pituitary extracts, bile salts). Hospitalized children are at increased risk for severe and complicated Salmonella infections, especially with drug-resistant organisms.

Pathogenesis

The estimated number of bacteria that must be ingested to cause symptomatic disease in healthy adults is 10⁶ to 10⁸ Salmonella organisms. The gastric acidity inhibits multiplication of the salmonellae, and most organisms are rapidly killed at gastric pH ≤2.0. Achlorhydria, buffering medications, rapid gastric emptying after gastrectomy or gastroenterostomy, and a large inoculum enable viable organisms to reach the small intestine. Neonates and young infants have hypochlorhydria and rapid gastric emptying, which contribute to their increased vulnerability to symptomatic salmonellosis. In infants who typically take fluids, the inoculum size required to produce disease is also comparatively smaller because of faster transit through the stomach.

Once they reach the small and large intestines, the ability of Salmonella organisms to multiply and cause infection depends on the infecting dose as well as competition with normal flora. Prior antibiotic therapy may alter this relationship, as might factors such as co-administration of antimotility agents. The typical intestinal mucosal response to nontyphoidal Salmonella infection is an enterocolitis with diffuse mucosal inflammation and edema, sometimes with erosions and microabscesses. Salmonella organisms are capable of penetrating the intestinal mucosa, although destruction of epithelial cells and ulcers are usually not found. Intestinal inflammation with polymorphonuclear leukocytes and macrophages usually involves the lamina propria. Underlying intestinal lymphoid tissue and mesenteric lymph nodes enlarge and may demonstrate small areas of necrosis. Such lymphoid hypertrophy may cause interference with the blood supply to the gut mucosa. Hyperplasia of the reticuloendothelial system (RES) is also found within the liver and spleen. If bacteremia develops, it may lead to localized infection and suppuration in almost any organ.

Although S. Typhimurium can cause systemic disease in humans, intestinal infection usually results in a localized enteritis that is associated with a secretory response in the intestinal epithelium. Intestinal infection also induces secretion of interleukin-8 (IL-8) from the basolateral surface and other chemoattractants from the apical surface, directing recruitment and transmigration of neutrophils into the gut lumen and thus preventing the systemic spread of the bacteria (Fig. 190-1).

Figure 190-1 On contact with the epithelial cell, salmonellae assemble the Salmonella pathogenicity island 1–encoded type III secretion system (TTSS-1) and translocate effectors (yellow spheres) into the eukaryotic cytoplasm. Effectors such as SopE, SopE2 and SopB then activate host Rho guanosine triphosphatase (GTPases), resulting in the rearrangement of the actin cytoskeleton into membrane ruffles, induction of mitogen-activated protein kinase (MAPK) pathways, and destabilization of tight junctions. Changes in the actin cytoskeleton, which are further modulated by the actin-binding proteins SipA and SipC, lead to bacterial uptake. MAPK signaling activates the transcription factors activator protein-1 (AP-1) and nuclear factor-κB (NF-κB), which turn on production of the proinflammatory polymorphonuclear leukocyte (PMN) chemokine interleukin (IL)-8. SipB induces caspase-1 activation in macrophages, with the release of IL-1β and IL-18, so augmenting the inflammatory response. In addition, SopB stimulates Cl^– secretion by its inositol phosphatase activity. The destabilization of tight junctions allows the transmigration of PMNs from the basolateral to the apical surface, paracellular fluid leakage, and access of bacteria to the basolateral surface. However, the transmigration of PMNs also occurs in the absence of tight-junction disruption and is further promoted by SopA. The actin cytoskeleton is restored, and MAPK signaling is turned off by the enzymatic activities of SptP. This also results in the down-modulation of inflammatory responses, to which SspH1 and AvrA also contribute by inhibiting activation of NF-κB.

(From Haraga A, Ohlson MB, Miller SI: Salmonellae interplay with host cells, Nat Rev Microbiol 6:53–66, 2008.)

Interestingly, virulence traits that contribute to the host response are common to all nontyphoidal Salmonella serovars. These include (1) the type III secretion system (TTSS-1) encoded on Salmonella pathogenicity island-1 (SP1), which mediates invasion of the intestinal epithelium; (2) the TTSS encoded on SP2 (TTSS-2), which is required for survival within macrophages; and (3) expression of strong agonists of innate pattern recognition receptors (lipopolysaccharide and flagellin), which are important for triggering an TLR-mediated inflammatory response mediated by Toll-like receptors (TLRs). These observations suggest that S. Typhimurium must have acquired additional factors that further modulate the host response during infection.

Salmonella species invade epithelial cells in vitro by a process of bacteria-mediated endocytosis involving cytoskeletal rearrangement, disruption of the epithelial cell brush border, and the subsequent formation of membrane ruffles (Fig. 190-2). An adherent and invasive phenotype of S. enterica is activated under conditions similar to those found in the human small intestine (high osmolarity, low oxygen). The invasive phenotype is mediated in part by Salmonella pathogenicity island 1, a 40-kb region that encodes regulator proteins such as HilA, the type 3 secretory system involved in invasion of epithelial cells, and a variety of other products. In humans the TLR-dependent interleukin-12/interferon-λ (IL-12/IFN-λ) is a major immunoregulatory system that bridges innate and adaptive immunity and is responsible for restricting the systemic spread of nontyphoidal Salmonella.

Figure 190-2 Formation of the Salmonella-containing vacuole (SCV) and induction of the Salmonella pathogenicity island 12 (SPI2) type III secretion system (TTSS) within the host cell. Shortly after internalization by macropinocytosis, salmonellae are enclosed in a spacious phagosome that is formed by membrane ruffles. Later, the phagosome fuses with lysosomes, acidifies, and shrinks to become adherent around the bacterium, and so is called the SCV. It contains the endocytic marker lysosomal associated membrane protein 1 (LAMP-1; purple). The Salmonella pathogenicity island 2 TTSS (TTSS-2) is induced within the SCV and translocates effector proteins (yellow spheres) across the phagosomal membrane several hours after phagocytosis. The TTSS-2 effectors SifA and PipB2 contribute to formation of Salmonella-induced filament along microtubules (green) and regulate microtubule-motor (yellow star shape) accumulation on the Sif and the SCV. SseJ is a deacylase that is active on the phagosome membrane. SseF and SseG cause microtubule bundling adjacent to the SCV and direct Golgi-derived vesicle traffic toward the SCV. Actin accumulates around the SCV in a TTSS-2–dependent manner, in which SspH2, SpvB, and SseI are thought to have a role.

(From Haraga A, Ohlson MB, Miller SI: Salmonellae interplay with host cells, Nat Rev Microbiol 6:53–66, 2008.)

Shortly following invasion of the gut epithelium, invasive Salmonella organisms encounter macrophages within the gut-associated lymphoid tissue. The interaction between Salmonella and macrophages results in alteration in the expression of a number of host genes, including those encoding proinflammatory mediators (inducible nitric oxide synthase [iNOS], chemokines, IL-1β), receptors or adhesion molecules (tumor necrosis factor-α receptor [TNF-αR], CD40, intercellular adhesion molecule 1 [ICAM-1]), and anti-inflammatory mediators (transforming growth factor-β1 and -β2 [TGF-β1] and TGF-β2). Other upregulated genes include those involved in cell death or apoptosis (intestinal epithelial cell protease, TNF-R1, Fas) and transcription factors (early growth response 1[Egr-1], IFN regulatory factor 1 [IRF-1]). S. Typhimurium can induce rapid macrophage death in vitro, which depends on the host cell protein caspase-1 and is mediated by the effector protein SipB (Salmonella invasion protein B). Intracellular S. Typhimurium is found within specialized Salmonella organisms containing vacuoles that have diverged from the normal endocytic pathway. This ability to survive within monocytes/macrophages is essential for S. Typhimurium to establish a systemic infection in the mouse. The mucosal proinflammatory response to S. Typhimurium infection and the subsequent recruitment of phagocytic cells to the site may also facilitate systemic spread of the bacteria.

Some virulence traits are shared by all salmonellae, but others are serotype restricted. These virulence traits have been defined in tissue culture and murine models, and it is likely that clinical features of human Salmonella infection will eventually be related to specific DNA sequences. With most diarrhea-associated nontyphoidal salmonelloses, the infection does not extend beyond the lamina propria and the local lymphatics. Specific virulence genes are related to the ability to cause bacteremia. These genes are found significantly more often in strains of S. Typhimurium isolated from the blood than in strains recovered from stool. Although both S. dublin and S. choleraesuis have a greater propensity to rapidly invade the bloodstream with little or no intestinal involvement, the development of disease after infection with Salmonella depends on the number of infecting organisms, their virulence traits, and several host defense factors. Various host factors may also affect the development of specific complications or clinical syndromes (Table 190-2) and of these, HIV infections are assuming greater importance in Africa in all age groups.

Bacteremia is possible with any Salmonella serotype, especially in individuals with reduced host defenses and especially in those with altered reticuloendothelial or cellular immune function. Thus, children with HIV infection, chronic granulomatous disease, and leukemia are more likely to demonstrate bacteremia after Salmonella infection, although the majority of children with Salmonella bacteremia in Africa are HIV negative. Children with Schistosoma mansoni

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