Significant Threats to Human Health

  • Christopher J. Silva
  • David L. Brandon
  • Craig B. Skinner
  • Xiaohua He
Part of the Food Microbiology and Food Safety book series (FMFS)


Shiga toxins represent a significant and evolving threat to human health. Shiga toxin-related illness is not a common foodborne illness, but it accounts for a disproportionately large share of hospitalizations and deaths. The phages that control expression of Shiga toxins can readily undergo recombination and incorporate new genetic information that can be passed on to their progeny. Because Shiga toxin-producing phages can infect bacteria other than E. coli, it is likely that new Shiga toxin-producing bacteria will emerge, such as the Enterobacter strain associated with a recent outbreak. Previous assumptions about pathogenicity have changed and will undoubtedly continue to change in the future. Based on prior research, the ability to attach and efface was considered to be essential for STEC pathogenicity, but the 2011 STEC outbreak in Germany demonstrated that a new strain (O104:H4), without attaching and effacing ability, could cause a major outbreak. New types of Shiga toxins are emerging, such as subtypes Stx2e and Stx2f that have a preference to bind Gb4. Changes in dietary patterns also influence the source and extent of outbreaks. Thus, the nature of the Shiga toxin threat is evolving on four levels: toxin structure, Stx-phages, bacterial serotypes/strains, and patterns of food production and consumption.


Enterobacter Hemolytic uremia syndrome (HUS) Thrombotic-thrombocytopenic purpura (TPP) Shigellosis Hemorrhagic colitis (HC) Intimin Attaching/effacing Enterohemorrhagic Escherichia coli (EHEC) Enteropathogenic Escherichia coli (EPEC) Antibiotic induction of SOS response 


  1. Al-Qarawi S, Fontaine RE, Al-Qahtani MS (1995) An outbreak of hemolytic uremic syndrome associated with antibiotic treatment of hospital inpatients for dysentery. Emerg Infect Dis 1(4):138–140CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bae WK, Lee YK, Cho MS, Ma SK, Kim SW, Kim NH, Choi KC (2006) A case of hemolytic uremic syndrome caused by Escherichia coli O104:H4. Yonsei Med J 47(3):437–439CrossRefPubMedPubMedCentralGoogle Scholar
  3. Basu D, Li XP, Kahn JN, May KL, Kahn PC, Tumer NE (2016) The A1 subunit of Shiga toxin 2 has higher affinity for ribosomes and higher catalytic activity than the A1 subunit of Shiga toxin 1. Infect Immun 84(1):149–161CrossRefGoogle Scholar
  4. Bennish ML, Khan WA, Begum M, Bridges EA, Ahmed S, Saha D, Salam MA, Acheson D, Ryan ET (2006) Low risk of hemolytic uremic syndrome after early effective antimicrobial therapy for Shigella dysenteriae type 1 infection in Bangladesh. Clin Infect Dis 42(3):356–362CrossRefPubMedGoogle Scholar
  5. Beutin L, Strauch E, Fischer I (1999) Isolation of Shigella sonnei lysogenic for a bacteriophage encoding gene for production of Shiga toxin. Lancet 353(9163):1498CrossRefPubMedGoogle Scholar
  6. Boerlin P, McEwen SA, Boerlin-Petzold F, Wilson JB, Johnson RP, Gyles CL (1999) Associations between virulence factors of Shiga toxin-producing Escherichia coli and disease in humans. J Clin Microbiol 37(3):497–503PubMedPubMedCentralGoogle Scholar
  7. Butler T (2012) Haemolytic uraemic syndrome during shigellosis. Trans R Soc Trop Med Hyg 106(7):395–399CrossRefPubMedGoogle Scholar
  8. Cassar CA, Ottaway M, Paiba GA, Futter R, Newbould S, Woodward MJ (2004) Absence of enteroaggregative Escherichia coli in farmed animals in Great Britain. Vet Rec 154(8):237–239CrossRefPubMedGoogle Scholar
  9. de Sablet T, Bertin Y, Vareille M, Girardeau JP, Garrivier A, Gobert AP, Martin C (2008) Differential expression of stx2 variants in Shiga toxin-producing Escherichia coli belonging to seropathotypes A and C. Microbiology 154(Pt 1):176–186CrossRefPubMedGoogle Scholar
  10. Dyve Lingelem AB, Hjelseth IA, Simm R, Torgersen ML, Sandvig K (2015) Geldanamycin enhances retrograde transport of Shiga toxin in HEp-2 cells. PLoS One 10(5):e0129214CrossRefPubMedGoogle Scholar
  11. Engedal N, Skotland T, Torgersen ML, Sandvig K (2011) Shiga toxin and its use in targeted cancer therapy and imaging. Microb Biotechnol 4(1):32–46CrossRefPubMedGoogle Scholar
  12. Frank C, Werber D, Cramer JP, Askar M, Faber M, an der Heiden M, Bernard H, Fruth A, Prager R, Spode A, Wadl M, Zoufaly A, Jordan S, Kemper MJ, Follin P, Muller L, King LA, Rosner B, Buchholz U, Stark K, Krause G (2011) Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 365(19):1771–1780CrossRefPubMedGoogle Scholar
  13. Fuller CA, Pellino CA, Flagler MJ, Strasser JE, Weiss AA (2011) Shiga toxin subtypes display dramatic differences in potency. Infect Immun 79(3):1329–1337CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gray MD, Lampel KA, Strockbine NA, Fernandez RE, Melton-Celsa AR, Maurelli AT (2014) Clinical isolates of Shiga toxin 1a-producing Shigella flexneri with an epidemiological link to recent travel to Hispaniola. Emerg Infect Dis 20(10):1669–1677CrossRefPubMedPubMedCentralGoogle Scholar
  15. Gupta SK, Strockbine N, Omondi M, Hise K, Fair MA, Mintz E (2007) Emergence of Shiga toxin 1 genes within Shigella dysenteriae type 4 isolates from travelers returning from the Island of Hispanola. Am J Trop Med Hyg 76(6):1163–1165PubMedGoogle Scholar
  16. Hale TL (1991) Genetic basis of virulence in Shigella species. Microbiol Rev 55(2):206–224PubMedPubMedCentralGoogle Scholar
  17. Hayashi T, Makino K, Ohnishi M, Kurokawa K, Ishii K, Yokoyama K, Han CG, Ohtsubo E, Nakayama K, Murata T, Tanaka M, Tobe T, Iida T, Takami H, Honda T, Sasakawa C, Ogasawara N, Yasunaga T, Kuhara S, Shiba T, Hattori M, Shinagawa H (2001) Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7 and genomic comparison with a laboratory strain K-12. DNA Res 8(1):11–22CrossRefPubMedGoogle Scholar
  18. He X, Quinones B, McMahon S, Mandrell RE (2012) A single-step purification and molecular characterization of functional Shiga toxin 2 variants from pathogenic Escherichia coli. Toxins 4(7):487–504CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kaper JB, Nataro JP, Mobley HL (2004) Pathogenic Escherichia coli. Nat Rev Microbiol 2(2):123–140CrossRefPubMedGoogle Scholar
  20. Keir LS, Marks SD, Kim JJ (2012) Shigatoxin-associated hemolytic uremic syndrome: current molecular mechanisms and future therapies. Drug Des Devel Ther 6:195–208PubMedPubMedCentralGoogle Scholar
  21. Keusch GT, Jacewicz M, Donohue-Rolfe A (1986) Pathogenesis of shigella diarrhea: evidence for an N-linked glycoprotein shigella toxin receptor and receptor modulation by beta-galactosidase. J Infect Dis 153(2):238–248CrossRefPubMedGoogle Scholar
  22. Kimmitt PT, Harwood CR, Barer MR (2000) Toxin gene expression by shiga toxin-producing Escherichia coli: the role of antibiotics and the bacterial SOS response. Emerg Infect Dis 6(5):458–465CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kleimann A, Toto S, Eberlein CK, Kielstein JT, Bleich S, Frieling H, Sieberer M (2014) Psychiatric symptoms in patients with Shiga toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome. PLoS One 9(7):e101839CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kotloff KL, Winickoff JP, Ivanoff B, Clemens JD, Swerdlow DL, Sansonetti PJ, Adak GK, Levine MM (1999) Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull World Health Organ 77(8):651–666PubMedPubMedCentralGoogle Scholar
  25. Kruger A, Lucchesi PM, Parma AE (2011) Verotoxins in bovine and meat verotoxin-producing Escherichia coli isolates: type, number of variants, and relationship to cytotoxicity. Appl Environ Microbiol 77(1):73–79CrossRefPubMedGoogle Scholar
  26. Lamba K, Nelson JA, Kimura AC, Poe A, Collins J, Kao AS, Cruz L, Inami G, Vaishampayan J, Garza A, Chaturvedi V, Vugia DJ (2016) Shiga toxin 1-producing Shigella sonnei infections, California, United States, 2014–2015. Emerg Infect Dis 22(4):679–686CrossRefPubMedPubMedCentralGoogle Scholar
  27. Magnus T, Rother J, Simova O, Meier-Cillien M, Repenthin J, Moller F, Gbadamosi J, Panzer U, Wengenroth M, Hagel C, Kluge S, Stahl RK, Wegscheider K, Urban P, Eckert B, Glatzel M, Fiehler J, Gerloff C (2012) The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak. Brain 135(Pt 6):1850–1859CrossRefPubMedGoogle Scholar
  28. Manning SD, Motiwala AS, Springman AC, Qi W, Lacher DW, Ouellette LM, Mladonicky JM, Somsel P, Rudrik JT, Dietrich SE, Zhang W, Swaminathan B, Alland D, Whittam TS (2008) Variation in virulence among clades of Escherichia coli O157:H7 associated with disease outbreaks. Proc Natl Acad Sci U S A 105(12):4868–4873CrossRefPubMedPubMedCentralGoogle Scholar
  29. Martinez-Castillo A, Allue-Guardia A, Dahbi G, Blanco J, Creuzburg K, Schmidt H, Muniesa M (2012) Type III effector genes and other virulence factors of Shiga toxin-encoding Escherichia coli isolated from wastewater. Environ Microbiol Rep 4(1):147–155CrossRefPubMedGoogle Scholar
  30. McDonough MA, Butterton JR (1999) Spontaneous tandem amplification and deletion of the Shiga toxin operon in Shigella dysenteriae 1. Mol Microbiol 34(5):1058–1069CrossRefPubMedGoogle Scholar
  31. Melton-Celsa A, Mohawk K, Teel L, O’Brien A (2012) Pathogenesis of Shiga-toxin producing Escherichia coli. Curr Top Microbiol Immunol 357:67–103PubMedGoogle Scholar
  32. Melton-Celsa AR (2014) Shiga toxin (Stx) classification, structure, and function. Microbiol Spectr 2(4):EHEC-0024-2013CrossRefGoogle Scholar
  33. Molbak K, Mead PS, Griffin PM (2002) Antimicrobial therapy in patients with Escherichia coli O157:H7 infection. JAMA 288(8):1014–1016CrossRefPubMedGoogle Scholar
  34. Nathanson S, Kwon T, Elmaleh M, Charbit M, Launay EA, Harambat J, Brun M, Ranchin B, Bandin F, Cloarec S, Bourdat-Michel G, Pietrement C, Champion G, Ulinski T, Deschenes G (2010) Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 5(7):1218–1228CrossRefPubMedPubMedCentralGoogle Scholar
  35. Newton HJ, Sloan J, Bulach DM, Seemann T, Allison CC, Tauschek M, Robins-Browne RM, Paton JC, Whittam TS, Paton AW, Hartland EL (2009) Shiga toxin-producing Escherichia coli strains negative for locus of enterocyte effacement. Emerg Infect Dis 15(3):372–380CrossRefPubMedPubMedCentralGoogle Scholar
  36. Obata F, Tohyama K, Bonev AD, Kolling GL, Keepers TR, Gross LK, Nelson MT, Sato S, Obrig TG (2008) Shiga toxin 2 affects the central nervous system through receptor globotriaosylceramide localized to neurons. J Infect Dis 198(9):1398–1406CrossRefPubMedPubMedCentralGoogle Scholar
  37. Obrig TG, Karpman D (2012) Shiga toxin pathogenesis: kidney complications and renal failure. Curr Top Microbiol Immunol 357:105–136PubMedPubMedCentralGoogle Scholar
  38. Olavesen KK, Lindstedt BA, Lobersli I, Brandal LT (2016) Expression of Shiga toxin 2 (Stx2) in highly virulent Stx-producing Escherichia coli (STEC) carrying different anti-terminator (q) genes. Microb Pathog 97:1–8CrossRefPubMedGoogle Scholar
  39. Ostroff SM, Tarr PI, Neill MA, Lewis JH, Hargrett-Bean N, Kobayashi JM (1989) Toxin genotypes and plasmid profiles as determinants of systemic sequelae in Escherichia coli O157:H7 infections. J Infect Dis 160(6):994–998CrossRefPubMedGoogle Scholar
  40. Percivalle E, Monzillo V, Pauletto A, Marone P, Imberti R (2016) Colistin inhibits E. coli O157:H7 Shiga-like toxin release, binds endotoxins and protects Vero cells. New Microbiol 39(2):119–123PubMedGoogle Scholar
  41. Perna NT, Mayhew GF, Posfai G, Elliott S, Donnenberg MS, Kaper JB, Blattner FR (1998) Molecular evolution of a pathogenicity island from enterohemorrhagic Escherichia coli O157:H7. Infect Immun 66(8):3810–3817PubMedPubMedCentralGoogle Scholar
  42. Pierard D, De Greve H, Haesebrouck F, Mainil J (2012) O157:H7 and O104:H4 Vero/Shiga toxin-producing Escherichia coli outbreaks: respective role of cattle and humans. Vet Res 43:13CrossRefPubMedPubMedCentralGoogle Scholar
  43. Ran XQ, Wang HZ, Liu JJ, Li S, Wang JF (2008) The immunogenicity of fusion protein linking the carboxyl terminus of the B subunit of Shiga toxin 2 to the B subunit of E. coli heat-labile enterotoxin. Vet Microbiol 127(1–2):209–215CrossRefPubMedGoogle Scholar
  44. Ren J, Utsunomiya I, Taguchi K, Ariga T, Tai T, Ihara Y, Miyatake T (1999) Localization of verotoxin receptors in nervous system. Brain Res 825(1–2):183–188CrossRefPubMedGoogle Scholar
  45. Sansonetti PJ (1992) Molecular and cellular biology of Shigella flexneri invasiveness: from cell assay systems to shigellosis. Curr Top Microbiol Immunol 180:1–19PubMedGoogle Scholar
  46. Scavia G, Morabito S, Tozzoli R, Michelacci V, Marziano ML, Minelli F, Ferreri C, Paglialonga F, Edefonti A, Caprioli A (2011) Similarity of Shiga toxin-producing Escherichia coli O104:H4 strains from Italy and Germany. Emerg Infect Dis 17(10):1957–1958CrossRefPubMedPubMedCentralGoogle Scholar
  47. Schuppner R, Maehlmann J, Dirks M, Worthmann H, Tryc AB, Sandorski K, Bahlmann E, Kielstein JT, Giesemann AM, Lanfermann H, Weissenborn K (2016) Neurological sequelae in adults after E coli O104: H4 infection-induced hemolytic-uremic syndrome. Medicine 95(6):e2337CrossRefPubMedPubMedCentralGoogle Scholar
  48. Siegler RL, Obrig TG, Pysher TJ, Tesh VL, Denkers ND, Taylor FB (2003) Response to Shiga toxin 1 and 2 in a baboon model of hemolytic uremic syndrome. Pediatr Nephrol 18(2):92–96PubMedGoogle Scholar
  49. Silva CJ, Erickson-Beltran ML, Skinner CB, Dynin I, Hui C, Patfield SA, Carter JM, He X (2014) Safe and effective means of detecting and quantitating Shiga-like toxins in attomole amounts. Anal Chem 86(10):4698–4706CrossRefPubMedGoogle Scholar
  50. Simova O, Weineck G, Schuetze T, Wegscheider K, Panzer U, Stahl RA, Gerloff C, Magnus T (2014) Neuropsychological outcome after complicated Shiga toxin-producing Escherichia coli infection. PLoS One 9(7):e103029CrossRefPubMedPubMedCentralGoogle Scholar
  51. Skinner C, McMahon S, Rasooly R, Carter JM, He X (2013) Purification and characterization of Shiga toxin 2f, an immunologically unrelated subtype of Shiga toxin 2. PLoS One 8(3):e59760. doi: 10.51371/journal.pone.0059760
  52. Soborg B, Lassen SG, Muller L, Jensen T, Ethelberg S, Molbak K, Scheutz F (2013) A verocytotoxin-producing E. coli outbreak with a surprisingly high risk of haemolytic uraemic syndrome, Denmark, September–October 2012. Euro Surveill 18(2)Google Scholar
  53. Tesh VL, Burris JA, Owens JW, Gordon VM, Wadolkowski EA, O’Brien AD, Samuel JE (1993) Comparison of the relative toxicities of Shiga-like toxins type I and type II for mice. Infect Immun 61(8):3392–3402PubMedPubMedCentralGoogle Scholar
  54. Thielman NM, Guerrant RL (2004) Clinical practice. Acute infectious diarrhea. N Engl J Med 350(1):38–47CrossRefPubMedGoogle Scholar
  55. Trachtman H, Austin C, Lewinski M, Stahl RA (2012) Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol 8(11):658–669CrossRefPubMedGoogle Scholar
  56. Uber AP, Trabulsi LR, Irino K, Beutin L, Ghilardi AC, Gomes TA, Liberatore AM, de Castro AF, Elias WP (2006) Enteroaggregative Escherichia coli from humans and animals differ in major phenotypical traits and virulence genes. FEMS Microbiol Lett 256(2):251–257CrossRefPubMedGoogle Scholar
  57. Uchida H, Kiyokawa N, Horie H, Fujimoto J, Takeda T (1999) The detection of Shiga toxins in the kidney of a patient with hemolytic uremic syndrome. Pediatr Res 45(1):133–137CrossRefPubMedGoogle Scholar
  58. Unkmeir A, Schmidt H (2000) Structural analysis of phage-borne stx genes and their flanking sequences in shiga toxin-producing Escherichia coli and Shigella dysenteriae type 1 strains. Infect Immun 68(9):4856–4864CrossRefPubMedPubMedCentralGoogle Scholar
  59. Veilleux S, Dubreuil JD (2006) Presence of Escherichia coli carrying the EAST1 toxin gene in farm animals. Vet Res 37(1):3–13CrossRefPubMedGoogle Scholar
  60. Wadolkowski EA, Sung LM, Burris JA, Samuel JE, O’Brien AD (1990) Acute renal tubular necrosis and death of mice orally infected with Escherichia coli strains that produce Shiga-like toxin type II. Infect Immun 58(12):3959–3965PubMedPubMedCentralGoogle Scholar
  61. Walterspiel JN, Ashkenazi S, Morrow AL, Cleary TG (1992) Effect of subinhibitory concentrations of antibiotics on extracellular Shiga-like toxin I. Infection 20(1):25–29CrossRefPubMedGoogle Scholar
  62. Wieler LH, Semmler T, Eichhorn I, Antao EM, Kinnemann B, Geue L, Karch H, Guenther S, Bethe A (2011) No evidence of the Shiga toxin-producing E. coli O104:H4 outbreak strain or enteroaggregative E. coli (EAEC) found in cattle faeces in northern Germany, the hotspot of the 2011 HUS outbreak area. Gut Pathog 3(1):17Google Scholar
  63. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI (2000) The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 342(26):1930–1936CrossRefPubMedPubMedCentralGoogle Scholar
  64. Zhang X, McDaniel AD, Wolf LE, Keusch GT, Waldor MK, Acheson DW (2000) Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J Infect Dis 181(2):664–670CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Christopher J. Silva
    • 1
  • David L. Brandon
    • 1
  • Craig B. Skinner
    • 1
  • Xiaohua He
    • 1
  1. 1.United States Department of Agriculture, Agricultural Research ServiceWestern Regional Research CenterAlbanyUSA

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