Pathogenesis of enteric (typhoid and paratyphoid) fever

Authors:: Jason Andrews, MD; Richelle C Charles, MD
Section Editor:: Stephen B Calderwood, MD
Deputy Editor:: Elinor L Baron, MD, DTMH

Literature review current through: Jan 2024.

This topic last updated: Jan 05, 2023.

INTRODUCTION — Enteric fever is characterized by severe systemic illness with fever and abdominal pain [1]. The organism classically responsible for the enteric fever syndrome is Salmonella enterica serotype Typhi (formerly S. typhi). Other Salmonella serotypes, particularly S. enterica serotypes Paratyphi A, B, or C, can cause a similar syndrome; however, it is usually not clinically useful or possible to reliably predict the causative organism based on clinical findings [2]. The term "enteric fever" is a collective term that refers to both typhoid and paratyphoid fever, and "typhoid" and "enteric fever" are often used interchangeably.

The pathogenesis of enteric fever will be reviewed here. The epidemiology, microbiology, clinical manifestations, diagnosis, treatment, and prevention of enteric fever are discussed separately. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis" and "Enteric (typhoid and paratyphoid) fever: Treatment and prevention" and "Immunizations for travel".)

PATHOGENESIS — The pathogenesis of enteric fever depends on a number of factors including the infecting species and infectious dose. Ingested organisms survive exposure to gastric acid before gaining access to the small bowel, where they penetrate the epithelium, enter the lymphoid tissue, and disseminate via the lymphatic or hematogenous route. A chronic carrier state is established in an estimated 1 to 5 percent of cases [1,3,4]. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Chronic carriers'.)

The organisms — The microbiology of organisms responsible for enteric fever is discussed separately. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Microbiology'.)

Unlike most S. enterica serovars, which have broad host ranges, typhoidal salmonellae are human-restricted pathogens, which has shaped their evolutionary history. For S. Typhi, multiple distinct lineages have evolved and spread regionally and globally; a large analysis of whole genome sequencing data revealed frequent international and intercontinental spread of S. Typhi strains, often carrying genetic determinants of antimicrobial resistance [5]. A multidrug-resistant lineage designated H58 emerged in the 1980s and quickly spread throughout Asia and Africa, becoming globally dominant. Also, long-term carriers may secrete S. Typhi variants with considerable genetic diversity [6]. Such changes may occur in response to antimicrobial therapy and/or host immune responses. Of note, S. Paratyphi A and S. Typhi have undergone convergent evolution through recombination and shared pseudogene formation [7].

Taken together, these studies suggest that S. Typhi evolves in response to environmental pressures, that especially virulent clones may exist, and that further study is needed to understand the specific virulence properties of this pathogen.

Infectious dose — Data on the numbers of S. Typhi organisms required to cause disease have been obtained from human volunteer studies and from epidemiologic investigations [8]. In general, the greater the infectious dose, the higher the attack rate and the shorter the incubation period. In a modern human challenge study, the Quailes strain was administered in bicarbonate solution to healthy volunteers and resulted in typhoid fever with documented bacteremia in 11 of 20 (55 percent) and 13 of 20 (65 percent) subjects who received 10³ and 10⁴ colony forming unit (CFU) doses, respectively [9]. The overall attack rate was 59 percent. Of note, a number of volunteers developed symptoms and had S. Typhi detected in their blood stream by polymerase chain reaction testing despite negative blood cultures, suggesting a possible overall attack rate of 73 percent [10].

It is difficult to generalize data obtained in experimental inoculations to actual ingestion of contaminated food and water; extrapolations from volunteer studies suggest that 10 to 20 percent of healthy individuals ingesting 10³ S. Typhi organisms will develop typhoid fever [11]. Data compiled from 12 outbreaks related to food, water, or occupational laboratory exposures showed "real life" infectious doses are usually low (<10³) with relatively low attack rates (averaging 4 percent) and fairly long incubation periods (12 to 21 days) [11]. Smaller numbers of organisms are likely to induce disease in high-risk individuals, such as those with achlorhydria (including that secondary to antacid use) or immunosuppressive illnesses such as AIDS [12].

Gastrointestinal infection — After ingestion, S. Typhi organisms that survive exposure to gastric acid gain access to the small bowel, where they penetrate the epithelium, enter the lymphoid tissue, and disseminate via the lymphatic or hematogenous route.

Diarrhea and constipation appear to occur with approximately equal frequency. The reasons for the variability in enteritis among Salmonella strains are not certain. In a cell culture model of gastroenteritis, nontyphoidal Salmonella strains associated with enteritis induced IL-8-mediated neutrophil transmigration across the epithelial cell; these observations were not seen with S. Typhi or other strains not associated with enteritis [13]. The muted IL-8 response and relative absence of neutrophil infiltration seen with S. Typhi may be mediated by Toll-like receptors and require the Vi capsular polysaccharide [14].

S. Typhi access the submucosal region of the bowel by two mechanisms: via the M-cell, a specialized epithelial cell that serves as a sampling and antigen presenting cell in the mucosa (or gut)-associated lymphoid system [15]; and via direct penetration into or around the epithelial cell itself [16-18]. The entry of S. Typhi into the epithelial cell appears to be mediated by the cystic fibrosis transmembrane conductance regulator (CFTR), the protein that is abnormal in cystic fibrosis. In one study, mice that were heterozygous for the most common CFTR mutation seen in cystic fibrosis in humans (Delta F508) translocated 86 percent fewer S. Typhi into the submucosa than wild-type mice; no translocation occurred in Delta 508 homozygous mice [19]. Genetic analyses of an Indonesian case-control cohort showed that a specific CFTR polymorphism known to affect CFTR protein expression appeared to confer modest protection against acquisition of enteric fever [20]. Thus, individuals who are heterozygous for CFTR may have a selective protection against typhoid fever.

S. Typhi proliferate in the submucosa, leading to hypertrophy of the Peyer's patches via recruitment of mononuclear cells and lymphocytes. Naïve subjects who developed typhoid fever after oral challenge had different patterns of monocyte and dendritic cell activation than those who did not develop illness [21]. Hypertrophy and subsequent necrosis of the submucosal tissues are probably responsible for abdominal pain and subsequent ileal perforation, a potentially fatal complication. Patients with enteric fever may develop "secondary" bacteremia with other organisms due to microscopic or macroscopic breaches in the intestinal mucosal barrier [22].

The potential role of typhoid toxin in disease pathogenesis is an area of investigative focus [23]. Typhoid toxin is a pyramidal holotoxin that contains a homopentamer of pertussis-like toxin B subunit (PltB) at its base, with pertussis-like toxin A (PltA; an adenosine diphosphate ribosyltransferase) in the center, and cytolethal distending toxin (CdtB; a DNase that results in cell cycle arrest) at the apex [24]. S. Typhi have uniquely evolved this toxin to adapt to humans and exclusively express the toxin while in vacuoles [25,26]. Injection of the toxin in animals causes many of the symptoms associated with enteric fever.

Systemic spread and persistence — Dissemination of S. Typhi from the Peyer's patches to the reticuloendothelial system occurs via the lymphatic system and bloodstream. Replication within the reticuloendothelial system is a hallmark of enteric fever and is responsible for the clinical findings of prostration, generalized sepsis, and hepatosplenomegaly. Some individuals contain the organism within the gastrointestinal system and do not become systemically ill but have persistent S. Typhi carriage [27,28].

Quantitative studies using density gradient separation of blood cells or buffy coat cultures from patients with typhoid fever demonstrated that S. Typhi isolated from blood cultures are frequently localized within the mononuclear cell-platelet layer [29,30]. Dissemination of the organisms via the blood stream occurs early in the course of illness; bacteremias are more frequently detected and are of higher grade during the first week of clinical illness [30].

Eventually, organisms reside within monocyte-derived or tissue macrophages in the liver, spleen, and bone marrow. The bone marrow is a clinical "sanctuary" for S. Typhi and a possible source of diagnostic culture material even after the initiation of antimicrobial therapy [31,32]. These intracellular organisms are likely sources for relapsing infection and late pyogenic complications, such as pericarditis, visceral abscesses, or osteomyelitis. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Other clinical manifestations'.)

Replete hemophagocytic macrophages may provide a niche for Salmonella persistence [33]. Acute experimentally-induced typhoid fever led to a rapid increase in the iron-regulatory hormone hepcidin and a decrease in serum iron and transferrin saturation [34]. It has also been proposed that the hemochromatosis C282Y mutation (present in up to 12.5 percent of northern and central Europeans) may confer resistance to infection with S. Typhi and mycobacteria, which require iron for growth in macrophages. Despite the total body iron overload, macrophages in C282Y homozygotes are low in iron. Hemochromatosis patients are not especially susceptible to salmonellosis or other intracellular infections, although they may be at increased risk for infection with other organisms, such as Vibrios [35,36].

Persistence of intracellular S. Typhi organisms within visceral and bone marrow macrophages has long been believed central to virulence. Molecular approaches to the study of the pathogenesis and persistence of S. Typhi have been facilitated by experiments with murine and human challenge models of typhoid fever and identified key genes and proteins [37-39]:

●The phoP/phoQ genes, which modulate transcriptional activation of bacterial proteins within macrophages, are important for full virulence; deletion of these genes markedly attenuated S. Typhi in human volunteers [40].

●Analysis of the S. Typhi proteome under conditions mimicking the intracellular macrophage environment identified a subset of highly expressed proteins unique to S. Typhi (versus nontyphoidal salmonellae) that likely play a role in pathogenesis and perhaps in human host specificity [41]. One protein identified was CdtB, which is the active component of the tripartite typhoid toxin that causes cell cycle arrest and DNA damage [42]. Typhoid toxin is a pyramidal holotoxin that contains a homopentamer of pertussis-like toxin B subunit (PltB) at its base, with pertussis-like toxin A (PltA; an adenosine diphosphate ribosyltransferase) in the center, and CdtB at the apex [24]. The potential role of typhoid toxin in disease pathogenesis is an area of investigative focus [23]. S. Typhi have uniquely evolved this toxin to adapt to humans and exclusively express the toxin while in vacuoles [25,26]. Injection of the toxin in animals causes many of the symptoms associated with enteric fever. In a human challenge model, individuals receiving a typhoid toxin deletion mutant, had a higher incidence of infection, shorter time to diagnosis, and longer duration of bacteremia compared with an isogenic wild-type strain [43]. These findings suggest that typhoid toxin is not essential for S. Typhi infection and might be important in modulating host immune responses

●Deletion of genes that facilitate colonization of deep tissues (cdt) [44], modulate adenylate cyclase levels (cya/crp) [45], or encode the synthesis of essential nutrients, such as purines (purA) [46] or aromatic amino acids (aroC/aroD) [45], also results in strains that are significantly attenuated in humans.

●In contrast, deletion of the Vi capsular polysaccharide (a protective polysaccharide antigen that serves as a parenteral typhoid fever vaccine [47,48]) did not result in significant attenuation of orally administered S. Typhi in volunteers [49]. Also, phenotypically Vi-negative isolates do cause typhoid fever [50], and Paratyphi A strains, which uniformly lack Vi, cause a clinical syndrome nearly indistinguishable from typhoid.

●Both S. Typhi and S. Paratyphi A appear to contain a Type VI secretion system (T6SS) that may give these typhoidal Salmonella a survival advantage against competing bacteria within the human gut [51].

Several S. Typhi mutants are currently being investigated as live vaccines for typhoid fever [40,44,46] and as vector microorganisms for delivery of other antigens to the gastrointestinal mucosal immune system.

Compared with S. Typhi, less is known about pathogenesis of Salmonella Paratyphi A, which lacks Vi polysaccharide, but does produce typhoid toxin. Evidence suggests that its long lipopolysaccharide O-antigen chains reduce inflammasome activation and pyroptosis, a form of programmed cell death, during infection of macrophages, a distinct mechanism of immune evasion from S. Typhi [52].

Host immunity/species specificity — Host immunologic defects, such as depressed cell-mediated immunity (eg, AIDS, glucocorticoid therapy) and altered phagocyte function (eg, sickle cell anemia, malaria), have not been associated with more severe or complicated typhoid infection [53,54]. In contrast, a variety of host immunologic defects are known to predispose to more severe and complicated illness due to nontyphoidal salmonellosis. (See "Pathogenesis of Salmonella gastroenteritis".)

There is some evidence that immunocompromised patients fare poorly with typhoidal infections, however. One study of four individuals with AIDS in Peru described atypically severe diarrhea or colitis [12]. Other case reports have documented unusual manifestations of S. Typhi infection, such as arteritis [55] or chorioamnionitis [56], in HIV-infected patients. Toll-like receptor 4 mutations might increase susceptibility to typhoid [57]; in contrast, variants in HLA-DRB1 appear to be associated with resistance to enteric fever [58]. Additionally, work from a human challenge model demonstrated that, in contrast to high titers of antibodies against S. Typhi, high levels of S. Typhi-responsive CD4 cells actually increase risk of developing typhoid disease upon exposure [59].

It has long been known that S. Typhi and Paratyphi A are uniquely human pathogens that do not affect other mammals (including laboratory mice), unlike nontyphoidal salmonellae. This appears to be related to fundamental differences in the way the innate and adaptive immune systems interact with these related organisms. Attempts at altering mice to render then susceptible to S. Typhi have been made. For instance, humanized mice (immunodeficient Rag2-/- γC-/- mice engrafted with human fetal liver hematopoietic cells or human umbilical cord stem cells) can be made susceptible to infection with S. Typhi [60,61]. Additionally, Rab GTPases, the recruitment of which are blocked in Salmonella Typhimurium, play a role in restricting growth of typhoidal Salmonella in nonhuman hosts [62]. These models recapitulate some important clinical features of human enteric fever and may be of some value for preliminary testing of typhoid vaccines.

With regard to the antigenic target associated with protective immunity in humans, IgG antibodies to the Vi polysaccharide have been shown to correlate with protection from infection and clinical disease in vaccine studies and controlled human challenge models [63-65]. However, protection from Vi-containing vaccines is incomplete; similarly, reinfection may occur following natural infection. Also, oral vaccination with an attenuated strain of S. Typhi (Ty21a) protects against typhoid fever even though Ty21a does not express Vi antigen. Bactericidal antibodies to O lipopolysaccharide (O-LPS) have also been shown to reduce disease severity but did not prevent infection [66]. In experimental challenge models, previous infection with S. Typhi provides some protection from rechallenge with S. Typhi, but no protection against heterologous challenge with S. Paratyphi A, and vice versa [67].

Chronic carriage — Chronic Salmonella carriage is defined as excretion of the organism in stool or urine >12 months after acute infection. Chronic carriage occurs more frequently in adult women and in patients with cholelithiasis or other biliary tract abnormalities [68,69]. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Chronic carriers'.)

Gallstones may serve as a persistent nidus of infection [68,69]. Gallstone biofilm has been observed in humans and mice, which appears to facilitate gallbladder colonization and shedding [70]. In animal and in vitro models, S. Typhi exposure to bile appears to induce formation of specific bacterial polysaccharide components that contribute to biofilm formation, and flagellar proteins may enhance bacterial adherence [71,72]. In rare cases, chronic carriage has been observed to persist even after antibiotic therapy and cholecystectomy, suggesting that factors other than biliary abnormalities may also contribute to the carrier state [73]. Urinary carriage is rare (3 percent of carriers) and is associated with nephrolithiasis and urinary tract abnormalities [74,75]. In areas where schistosomiasis is highly endemic, rates of urinary carriage can be higher [76].

In general, chronic carriers do not develop recurrent symptomatic disease. They appear to reach an immunologic equilibrium in which they are chronically colonized and may excrete large numbers of organisms, but have a high level of immunity and do not develop clinical disease [3,77-79]. Chronic carriers frequently have high serum antibody titers against the Vi antigen; some studies have found Vi serology to be a useful test for rapid identification of such patients [80,81], while others have not [82]. Immune responses targeting the protein YncE have been identified to identify chronic carriers in Nepal; additional investigation is required to further evaluate the utility of this marker [83]. Susceptibility to colonization with S. Typhi may also be related to blood group antigens [69]. S. Typhi may undergo substantial evolution during carriage, dropping genes responsible for Vi production, replicating more slowly in culture, and forming significantly thicker biofilms, compared with reference strains [84,85].

The S. Typhi carrier state may be an independent risk factor for carcinoma of the gallbladder as well as other cancers [86,87], perhaps as a result of activating MAPK and AKT pathways [88]. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis".)

Chronic carriage may also result from infection with S. Paratyphi strains, which has been isolated from Nepalese cholecystectomy samples almost as frequently as S. Typhi. [89]. (See "Nontyphoidal Salmonella: Gastrointestinal infection and asymptomatic carriage".)

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SUMMARY

●Ingested Salmonella Typhi organisms survive exposure to gastric acid before gaining access to the small bowel, where they penetrate the epithelium, enter the lymphoid tissue, and disseminate via the lymphatic or hematogenous route. A chronic carrier state is established in a minority of cases. (See 'Pathogenesis' above.)

●In general, the greater the S. Typhi infectious dose, the higher the attack rate and the shorter the incubation period. Infectious doses are usually low (<10³) with relatively low attack rates (averaging 4 percent) and fairly long incubation periods (12 to 21 days). (See 'Infectious dose' above.)

●Dissemination of S. Typhi from the Peyer's patches to the reticuloendothelial system occurs via the lymphatic system and bloodstream. Eventually, organisms reside within tissue macrophages in the liver, spleen, and bone marrow. These intracellular organisms are likely sources for relapsing infection and late pyogenic complications. (See 'Systemic spread and persistence' above.)

●Host immunologic defects such as depressed cell-mediated immunity and altered phagocyte function have not generally been associated with more severe or complicated typhoid infection. However, there is some evidence that immunocompromised patients fare poorly with typhoidal infections. (See 'Host immunity/species specificity' above.)

●Chronic carriage occurs more frequently in women and in patients with cholelithiasis or other biliary tract abnormalities. S. Typhi exposure to bile appears to induce formation of specific bacterial polysaccharide components that contribute to biofilm formation, and flagellar proteins may enhance bacterial adherence. (See 'Chronic carriage' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Elizabeth L Hohmann, MD, and Edward T Ryan, MD, DTMH, who contributed to earlier versions of this topic review.

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Topic 2703 Version 28.0

خرید پکیج

Pathogenesis of enteric (typhoid and paratyphoid) fever

References