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Pathogenesis of enteric (typhoid and paratyphoid) fever

Edward T Ryan, MD, DTMH
Jason Andrews, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Allyson Bloom, MD


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 "Epidemiology, microbiology, clinical manifestations, and diagnosis of enteric (typhoid and paratyphoid) fever" and "Treatment and prevention of enteric (typhoid and paratyphoid) fever" and "Immunizations for travel".)


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 "Epidemiology, microbiology, clinical manifestations, and diagnosis of enteric (typhoid and paratyphoid) fever", section on 'Chronic carriers'.)

The organisms — The microbiology of organisms responsible for enteric fever is discussed separately. (See "Epidemiology, microbiology, clinical manifestations, and diagnosis of enteric (typhoid and paratyphoid) fever", 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. It has been suggested that S. Typhi represents a single clone with little intraspecies divergence [5,6]. However, other studies have demonstrated that the S. Typhi genome has undergone significant evolutionary rearrangement [7,8]. Differences have been found among isolates of S. Typhi in pulsed field gel electrophoretic (PFGE) patterns, outer membrane protein profiles [9] and ribotypes [10]. Certain flagellar serotypes [11] and PFGE patterns [12] have been associated with more severe clinical illness and greater antibiotic resistance in endemic areas. Bacterial whole-genome sequence analysis has identified a dominant multidrug-resistant lineage designated H58 that has emerged and spread through Asia and Africa over the past 30 years [13]. Also, long term carriers may secrete S. Typhi variants with considerable genetic diversity [14]. 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 [15].

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Literature review current through: Nov 2017. | This topic last updated: Nov 27, 2017.
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  1. Parry CM, Hien TT, Dougan G, et al. Typhoid fever. N Engl J Med 2002; 347:1770.
  2. Vollaard AM, Ali S, Widjaja S, et al. Identification of typhoid fever and paratyphoid fever cases at presentation in outpatient clinics in Jakarta, Indonesia. Trans R Soc Trop Med Hyg 2005; 99:440.
  3. Dham SK, Thompson RA. Humoral and cell-mediated immune responses in chronic typhoid carriers. Clin Exp Immunol 1982; 50:34.
  4. Levine MM, Black RE, Lanata C. Precise estimation of the numbers of chronic carriers of Salmonella typhi in Santiago, Chile, an endemic area. J Infect Dis 1982; 146:724.
  5. Reeves MW, Evins GM, Heiba AA, et al. Clonal nature of Salmonella typhi and its genetic relatedness to other salmonellae as shown by multilocus enzyme electrophoresis, and proposal of Salmonella bongori comb. nov. J Clin Microbiol 1989; 27:313.
  6. Selander RK, Beltran P, Smith NH, et al. Evolutionary genetic relationships of clones of Salmonella serovars that cause human typhoid and other enteric fevers. Infect Immun 1990; 58:2262.
  7. Liu SL, Sanderson KE. Rearrangements in the genome of the bacterium Salmonella typhi. Proc Natl Acad Sci U S A 1995; 92:1018.
  8. Liu SL, Sanderson KE. Highly plastic chromosomal organization in Salmonella typhi. Proc Natl Acad Sci U S A 1996; 93:10303.
  9. Franco A, Gonzalez C, Levine OS, et al. Further consideration of the clonal nature of Salmonella typhi: evaluation of molecular and clinical characteristics of strains from Indonesia and Peru. J Clin Microbiol 1992; 30:2187.
  10. Altwegg M, Hickman-Brenner FW, Farmer JJ 3rd. Ribosomal RNA gene restriction patterns provide increased sensitivity for typing Salmonella typhi strains. J Infect Dis 1989; 160:145.
  11. Grossman DA, Witham ND, Burr DH, et al. Flagellar serotypes of Salmonella typhi in Indonesia: relationships among motility, invasiveness, and clinical illness. J Infect Dis 1995; 171:212.
  12. Dutta S, Das S, Mitra U, et al. Antimicrobial resistance, virulence profiles and molecular subtypes of Salmonella enterica serovars Typhi and Paratyphi A blood isolates from Kolkata, India during 2009-2013. PLoS One 2014; 9:e101347.
  13. Wong VK, Baker S, Pickard DJ, et al. Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events. Nat Genet 2015; 47:632.
  14. Chiou CS, Wei HL, Mu JJ, et al. Salmonella enterica serovar Typhi variants in long-term carriers. J Clin Microbiol 2013; 51:669.
  15. Holt KE, Thomson NR, Wain J, et al. Pseudogene accumulation in the evolutionary histories of Salmonella enterica serovars Paratyphi A and Typhi. BMC Genomics 2009; 10:36.
  16. Waddington CS, Darton TC, Woodward WE, et al. Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies. J Infect 2014; 68:405.
  17. Waddington CS, Darton TC, Jones C, et al. An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin Infect Dis 2014; 58:1230.
  18. Darton TC, Zhou L, Blohmke CJ, et al. Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia. J Infect 2017; 74:358.
  19. Blaser MJ, Newman LS. A review of human salmonellosis: I. Infective dose. Rev Infect Dis 1982; 4:1096.
  20. Gotuzzo E, Frisancho O, Sanchez J, et al. Association between the acquired immunodeficiency syndrome and infection with Salmonella typhi or Salmonella paratyphi in an endemic typhoid area. Arch Intern Med 1991; 151:381.
  21. McCormick BA, Miller SI, Carnes D, Madara JL. Transepithelial signaling to neutrophils by salmonellae: a novel virulence mechanism for gastroenteritis. Infect Immun 1995; 63:2302.
  22. Raffatellu M, Chessa D, Wilson RP, et al. The Vi capsular antigen of Salmonella enterica serotype Typhi reduces Toll-like receptor-dependent interleukin-8 expression in the intestinal mucosa. Infect Immun 2005; 73:3367.
  23. Kohbata S, Yokoyama H, Yabuuchi E. Cytopathogenic effect of Salmonella typhi GIFU 10007 on M cells of murine ileal Peyer's patches in ligated ileal loops: an ultrastructural study. Microbiol Immunol 1986; 30:1225.
  24. Kops SK, Lowe DK, Bement WM, West AB. Migration of Salmonella typhi through intestinal epithelial monolayers: an in vitro study. Microbiol Immunol 1996; 40:799.
  25. Mills SD, Finlay BB. Comparison of Salmonella typhi and Salmonella typhimurium invasion, intracellular growth and localization in cultured human epithelial cells. Microb Pathog 1994; 17:409.
  26. Tartera C, Metcalf ES. Osmolarity and growth phase overlap in regulation of Salmonella typhi adherence to and invasion of human intestinal cells. Infect Immun 1993; 61:3084.
  27. Pier GB, Grout M, Zaidi T, et al. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 1998; 393:79.
  28. van de Vosse E, de Visser AW, Al-Attar S, et al. Distribution of CFTR variations in an Indonesian enteric fever cohort. Clin Infect Dis 2010; 50:1231.
  29. Toapanta FR, Bernal PJ, Fresnay S, et al. Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis 2015; 9:e0003837.
  30. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N Engl J Med 1984; 310:82.
  31. Galán JE. Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi. Proc Natl Acad Sci U S A 2016; 113:6338.
  32. Fowler CC, Chang SJ, Gao X, et al. Emerging insights into the biology of typhoid toxin. Curr Opin Microbiol 2017; 35:70.
  33. Hornick RB, Greisman SE, Woodward TE, et al. Typhoid fever: pathogenesis and immunologic control. N Engl J Med 1970; 283:686.
  34. Meals RA. Paratyphoid fever: a report of 62 cases with several unusual findings and a review of the literature. Arch Intern Med 1976; 136:1422.
  35. Rubin FA, McWhirter PD, Burr D, et al. Rapid diagnosis of typhoid fever through identification of Salmonella typhi within 18 hours of specimen acquisition by culture of the mononuclear cell-platelet fraction of blood. J Clin Microbiol 1990; 28:825.
  36. Wain J, Diep TS, Ho VA, et al. Quantitation of bacteria in blood of typhoid fever patients and relationship between counts and clinical features, transmissibility, and antibiotic resistance. J Clin Microbiol 1998; 36:1683.
  37. Gasem MH, Dolmans WM, Isbandrio BB, et al. Culture of Salmonella typhi and Salmonella paratyphi from blood and bone marrow in suspected typhoid fever. Trop Geogr Med 1995; 47:164.
  38. Guerra-Caceres JG, Gotuzzo-Herencia E, Crosby-Dagnino E, et al. Diagnostic value of bone marrow culture in typhoid fever. Trans R Soc Trop Med Hyg 1979; 73:680.
  39. Nix RN, Altschuler SE, Henson PM, Detweiler CS. Hemophagocytic macrophages harbor Salmonella enterica during persistent infection. PLoS Pathog 2007; 3:e193.
  40. Darton TC, Blohmke CJ, Giannoulatou E, et al. Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans. PLoS Negl Trop Dis 2015; 9:e0004029.
  41. Weinberg ED. Survival advantage of the hemochromatosis C282Y mutation. Perspect Biol Med 2008; 51:98.
  42. Moalem S, Weinberg ED, Percy ME. Hemochromatosis and the enigma of misplaced iron: implications for infectious disease and survival. Biometals 2004; 17:135.
  43. Fields PI, Swanson RV, Haidaris CG, Heffron F. Mutants of Salmonella typhimurium that cannot survive within the macrophage are avirulent. Proc Natl Acad Sci U S A 1986; 83:5189.
  44. Groisman EA, Chiao E, Lipps CJ, Heffron F. Salmonella typhimurium phoP virulence gene is a transcriptional regulator. Proc Natl Acad Sci U S A 1989; 86:7077.
  45. Miller SI, Kukral AM, Mekalanos JJ. A two-component regulatory system (phoP phoQ) controls Salmonella typhimurium virulence. Proc Natl Acad Sci U S A 1989; 86:5054.
  46. Hohmann EL, Oletta CA, Killeen KP, Miller SI. phoP/phoQ-deleted Salmonella typhi (Ty800) is a safe and immunogenic single-dose typhoid fever vaccine in volunteers. J Infect Dis 1996; 173:1408.
  47. Ansong C, Yoon H, Norbeck AD, et al. Proteomics analysis of the causative agent of typhoid fever. J Proteome Res 2008; 7:546.
  48. Spanò S, Ugalde JE, Galán JE. Delivery of a Salmonella Typhi exotoxin from a host intracellular compartment. Cell Host Microbe 2008; 3:30.
  49. Nardelli-Haefliger D, Kraehenbuhl JP, Curtiss R 3rd, et al. Oral and rectal immunization of adult female volunteers with a recombinant attenuated Salmonella typhi vaccine strain. Infect Immun 1996; 64:5219.
  50. Tacket CO, Hone DM, Curtiss R 3rd, et al. Comparison of the safety and immunogenicity of delta aroC delta aroD and delta cya delta crp Salmonella typhi strains in adult volunteers. Infect Immun 1992; 60:536.
  51. Levine MM, Herrington D, Murphy JR, et al. Safety, infectivity, immunogenicity, and in vivo stability of two attenuated auxotrophic mutant strains of Salmonella typhi, 541Ty and 543Ty, as live oral vaccines in humans. J Clin Invest 1987; 79:888.
  52. Acharya IL, Lowe CU, Thapa R, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. A preliminary report. N Engl J Med 1987; 317:1101.
  53. Plotkin SA, Bouveret-Le Cam N. A new typhoid vaccine composed of the Vi capsular polysaccharide. Arch Intern Med 1995; 155:2293.
  54. Hone DM, Attridge SR, Forrest B, et al. A galE via (Vi antigen-negative) mutant of Salmonella typhi Ty2 retains virulence in humans. Infect Immun 1988; 56:1326.
  55. Pulickal AS, Callaghan MJ, Kelly DF, et al. Prevalence and genetic analysis of phenotypically Vi- negative Salmonella typhi isolates in children from Kathmandu, Nepal. J Trop Pediatr 2013; 59:317.
  56. Levine MM, Farag TH. Invasive salmonella infections and HIV in Northern Tanzania. Clin Infect Dis 2011; 52:349.
  57. Crump JA, Ramadhani HO, Morrissey AB, et al. Invasive bacterial and fungal infections among hospitalized HIV-infected and HIV-uninfected adults and adolescents in northern Tanzania. Clin Infect Dis 2011; 52:341.
  58. Houston S. Salmonella typhi bacteremia and HIV infection with common iliac artery occlusion. Cent Afr J Med 1994; 40:48.
  59. Hedriana HL, Mitchell JL, Williams SB. Salmonella typhi chorioamnionitis in a human immunodeficiency virus-infected pregnant woman. A case report. J Reprod Med 1995; 40:157.
  60. Nguyen TH, Mai NL, Le TP, et al. Toll-like receptor 4 (TLR4) and typhoid fever in Vietnam. PLoS One 2009; 4:e4800.
  61. Dunstan SJ, Hue NT, Han B, et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet 2014; 46:1333.
  62. Fresnay S, McArthur MA, Magder LS, et al. Importance of Salmonella Typhi-Responsive CD8+ T Cell Immunity in a Human Typhoid Fever Challenge Model. Front Immunol 2017; 8:208.
  63. Mathur R, Oh H, Zhang D, et al. A mouse model of Salmonella typhi infection. Cell 2012; 151:590.
  64. Song J, Willinger T, Rongvaux A, et al. A mouse model for the human pathogen Salmonella typhi. Cell Host Microbe 2010; 8:369.
  65. Firoz Mian M, Pek EA, Chenoweth MJ, Ashkar AA. Humanized mice are susceptible to Salmonella typhi infection. Cell Mol Immunol 2011; 8:83.
  66. Spanò S, Gao X, Hannemann S, et al. A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP. Cell Host Microbe 2016; 19:216.
  67. Lai CW, Chan RC, Cheng AF, et al. Common bile duct stones: a cause of chronic salmonellosis. Am J Gastroenterol 1992; 87:1198.
  68. Hofmann E, Chianale J, Rollán A, et al. Blood group antigen secretion and gallstone disease in the Salmonella typhi chronic carrier state. J Infect Dis 1993; 167:993.
  69. Crawford RW, Rosales-Reyes R, Ramírez-Aguilar Mde L, et al. Gallstones play a significant role in Salmonella spp. gallbladder colonization and carriage. Proc Natl Acad Sci U S A 2010; 107:4353.
  70. Crawford RW, Gibson DL, Kay WW, Gunn JS. Identification of a bile-induced exopolysaccharide required for Salmonella biofilm formation on gallstone surfaces. Infect Immun 2008; 76:5341.
  71. Crawford RW, Reeve KE, Gunn JS. Flagellated but not hyperfimbriated Salmonella enterica serovar Typhimurium attaches to and forms biofilms on cholesterol-coated surfaces. J Bacteriol 2010; 192:2981.
  72. Ristori C, Rodríguez H, Vicent P, et al. Persistence of the Salmonella typhi-paratyphi carrier state after gallbladder removal. Bull Pan Am Health Organ 1982; 16:361.
  74. Taylor DN, Pollard RA, Blake PA. Typhoid in the United States and the risk to the international traveler. J Infect Dis 1983; 148:599.
  75. Høj L, Binder V, Espersen F, et al. Secretion rates of immunoglobulins, albumin, haptoglobin and complement factors C3 and C4 in the perfused jejunum and ileum of human Salmonella carriers. Acta Pathol Microbiol Immunol Scand C 1984; 92:129.
  76. Lanata CF, Levine MM, Ristori C, et al. Vi serology in detection of chronic Salmonella typhi carriers in an endemic area. Lancet 1983; 2:441.
  77. Lin FY, Becke JM, Groves C, et al. Restaurant-associated outbreak of typhoid fever in Maryland: identification of carrier facilitated by measurement of serum Vi antibodies. J Clin Microbiol 1988; 26:1194.
  78. Gupta A, My Thanh NT, Olsen SJ, et al. Evaluation of community-based serologic screening for identification of chronic Salmonella typhi carriers in Vietnam. Int J Infect Dis 2006; 10:309.
  79. Charles RC, Sultana T, Alam MM, et al. Identification of immunogenic Salmonella enterica serotype Typhi antigens expressed in chronic biliary carriers of S. Typhi in Kathmandu, Nepal. PLoS Negl Trop Dis 2013; 7:e2335.
  80. Caygill CP, Braddick M, Hill MJ, et al. The association between typhoid carriage, typhoid infection and subsequent cancer at a number of sites. Eur J Cancer Prev 1995; 4:187.
  81. Nagaraja V, Eslick GD. Systematic review with meta-analysis: the relationship between chronic Salmonella typhi carrier status and gall-bladder cancer. Aliment Pharmacol Ther 2014; 39:745.
  82. Scanu T, Spaapen RM, Bakker JM, et al. Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma. Cell Host Microbe 2015; 17:763.
  83. Dongol S, Thompson CN, Clare S, et al. The microbiological and clinical characteristics of invasive salmonella in gallbladders from cholecystectomy patients in kathmandu, Nepal. PLoS One 2012; 7:e47342.