Skip to main content
SpringerLink
Log in

Oral administration of Shiga toxin-producing Escherichia coli induces intestinal and systemic specific immune response in mice

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Hemolytic uremic syndrome (HUS) is the major complication of gastrointestinal infections with enterohemorrhagic Escherichia coli (EHEC) and is mediated by the production of Shiga toxins (Stx). Although it has been previously reported that not only HUS patients but healthy children have anti-Stx antibodies, very little is known about how these infections impact on mucosal immune system to generate a specific immune response. This work aimed to evaluate the immune responses elicited after a single oral dose of EHEC in a mouse model of HUS at weaning. We found sequential activation of T and B lymphocytes together with an increased percentage of IgA-bearing B cells in Peyer’s patches and mesenteric lymph nodes. We also found fecal anti-EHEC IgA and serum anti-Stx2 IgG in EHEC-inoculated mice. Besides, these mice were partially protected against an intravenous challenge with Stx2. These data demonstrate that one episode of EHEC infection is enough to induce activation in the gut-associated lymphoid tissue, especially the B cell compartment, and lead to the production of specific IgA in mucosal tissue and the generation of systemic protection against Stx2 in a percentage of intragastrically inoculated mice. These data also support the epidemiologic observation that a second episode of HUS is very rare.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Paton JC, Paton AW (1998) Pathogenesis and diagnosis of Shiga toxin-producing Escherichia coli infections. Clin Microbiol Rev 11(3):450–479

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Rivas M, Miliwebsky E, Chinen I, Deza N, Leotta GA (2006) The epidemiology of hemolytic uremic syndrome in Argentina. Diagnosis of the etiologic agent, reservoirs and routes of transmission. Medicina (B Aires) 66(Suppl 3):27–32

    Google Scholar 

  3. Johnson KE, Thorpe CM, Sears CL (2006) The emerging clinical importance of non-O157 Shiga toxin-producing Escherichia coli. Clin Infect Dis 43(12):1587–1595

    Article  PubMed  Google Scholar 

  4. Rivas M, Padola NL, Lucchesi PMA, Masana M (2010) Diarrheagenic Escherichia coli in Argentina. In: Torres AG (ed) Pathogenic Escherichia coli in Latin America. Bentham Science Publishers Ltd., Oak Park, pp 142–161

    Google Scholar 

  5. Fernandez-Brando RJ, Bentancor LV, Mejias MP, Ramos MV, Exeni A, Exeni C, Laso Mdel C, Exeni R, Isturiz MA, Palermo MS (2010) Antibody response to Shiga toxins in Argentinean children with enteropathic hemolytic uremic syndrome at acute and long-term follow-up periods. PLoS One 6(4):e19136

    Article  Google Scholar 

  6. Ludwig K, Karmali MA, Sarkim V, Bobrowski C, Petric M, Karch H, Muller-Wiefel DE (2001) Antibody response to Shiga toxins Stx2 and Stx1 in children with enteropathic hemolytic-uremic syndrome. J Clin Microbiol 39(6):2272–2279

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Karmali MA, Mascarenhas M, Petric M, Dutil L, Rahn K, Ludwig K, Arbus GS, Michel P, Sherman PM, Wilson J, Johnson R, Kaper JB (2003) Age-specific frequencies of antibodies to Escherichia coli verocytotoxins (Shiga toxins) 1 and 2 among urban and rural populations in southern Ontario. J Infect Dis 188(11):1724–1729

    Article  CAS  PubMed  Google Scholar 

  8. Rivas M, Miliwebsky E, Chinen I, Roldan CD, Balbi L, Garcia B, Fiorilli G, Sosa-Estani S, Kincaid J, Rangel J, Griffin PM (2006) Characterization and epidemiologic subtyping of Shiga toxin-producing Escherichia coli strains isolated from hemolytic uremic syndrome and diarrhea cases in Argentina. Foodborne Pathog Dis 3(1):88–96

    Article  CAS  PubMed  Google Scholar 

  9. Masana MO, Leotta GA, Del Castillo LL, D’Astek BA, Palladino PM, Galli L, Vilacoba E, Carbonari C, Rodriguez HR, Rivas M (2010) Prevalence, characterization, and genotypic analysis of Escherichia coli O157:H7/NM from selected beef exporting abattoirs of Argentina. J Food Prot 73(4):649–656

    Google Scholar 

  10. Mowat AM (2003) Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 3(4):331–341

    Article  CAS  PubMed  Google Scholar 

  11. Cerutti A, Rescigno M (2008) The biology of intestinal immunoglobulin A responses. Immunity 28(6):740–750

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Alpan O, Rudomen G, Matzinger P (2001) The role of dendritic cells, B cells, and M cells in gut-oriented immune responses. J Immunol 166(8):4843–4852

    Article  CAS  PubMed  Google Scholar 

  13. Mora JR, von Andrian UH (2008) Differentiation and homing of IgA-secreting cells. Mucosal Immunol 1(2):96–109

    Article  CAS  PubMed  Google Scholar 

  14. Butcher EC, Rouse RV, Coffman RL, Nottenburg CN, Hardy RR, Weissman IL (1982) Surface phenotype of Peyer’s patch germinal center cells: implications for the role of germinal centers in B cell differentiation. J Immunol 129(6):2698–2707

    CAS  PubMed  Google Scholar 

  15. Glick AB, McCune BK, Abdulkarem N, Flanders KC, Lumadue JA, Smith JM, Sporn MB (1991) Complex regulation of TGF beta expression by retinoic acid in the vitamin A-deficient rat. Development 111(4):1081–1086

    CAS  PubMed  Google Scholar 

  16. Coffman RL, Lebman DA, Shrader B (1989) Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med 170(3):1039–1044

    Article  CAS  PubMed  Google Scholar 

  17. Tseng J (1984) A population of resting IgM-IgD double-bearing lymphocytes in Peyer’s patches: the major precursor cells for IgA plasma cells in the gut lamina propria. J Immunol 132(6):2730–2735

    CAS  PubMed  Google Scholar 

  18. Martinoli C, Chiavelli A, Rescigno M (2007) Entry route of Salmonella typhimurium directs the type of induced immune response. Immunity 27(6):975–984

    Article  CAS  PubMed  Google Scholar 

  19. Ibarra C, Palermo MS (2010) Host Response to Pathogenic Escherichia coli. In: Torres AG (ed) Pathogenic Escherichia coli in Latin America. Bentham Science Publishers Ltd, Sharjah, pp 122–141. ISBN 978-1-60805-192-2

    Google Scholar 

  20. Simmons CP, Goncalves NS, Ghaem-Maghami M, Bajaj-Elliott M, Clare S, Neves B, Frankel G, Dougan G, MacDonald TT (2002) Impaired resistance and enhanced pathology during infection with a noninvasive, attaching-effacing enteric bacterial pathogen, Citrobacter rodentium, in mice lacking IL-12 or IFN-gamma. J Immunol 168(4):1804–1812

    Article  CAS  PubMed  Google Scholar 

  21. Brando RJ, Miliwebsky E, Bentancor L, Deza N, Baschkier A, Ramos MV, Fernandez GC, Meiss R, Rivas M, Palermo MS (2008) Renal damage and death in weaned mice after oral infection with Shiga toxin 2-producing Escherichia coli strains. Clin Exp Immunol 153(2):297–306

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Nagano K, Taguchi K, Hara T, Yokoyama S, Kawada K, Mori H (2003) Adhesion and colonization of enterohemorrhagic Escherichia coli O157:H7 in cecum of mice. Microbiol Immunol 47(2):125–132

    Article  CAS  PubMed  Google Scholar 

  23. Fernandez MI, Thuizat A, Pedron T, Neutra M, Phalipon A, Sansonetti PJ (2003) A newborn mouse model for the study of intestinal pathogenesis of shigellosis. Cell Microbiol 5(7):481–491

    Article  CAS  PubMed  Google Scholar 

  24. Keren DF, Brown JE, McDonald RA, Wassef JS (1989) Secretory immunoglobulin A response to Shiga toxin in rabbits: kinetics of the initial mucosal immune response and inhibition of toxicity in vitro and in vivo. Infect Immun 57(7):1885–1889

    CAS  PubMed Central  PubMed  Google Scholar 

  25. McQueen CE, Boedeker EC, Le M, Hamada Y, Brown WR (1992) Mucosal immune response to RDEC-1 infection: study of lamina propria antibody-producing cells and biliary antibody. Infect Immun 60(1):206–212

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Cohen A, Madrid-Marina V, Estrov Z, Freedman MH, Lingwood CA, Dosch HM (1990) Expression of glycolipid receptors to Shiga-like toxin on human B lymphocytes: a mechanism for the failure of long-lived antibody response to dysenteric disease. Int Immunol 2(1):1–8

    Article  CAS  PubMed  Google Scholar 

  27. Van Amersfoort ES, Van Berkel TJ, Kuiper J (2003) Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clin Microbiol Rev 16(3):379–414

    Article  PubMed Central  PubMed  Google Scholar 

  28. Castellanos MC, Munoz C, Montoya MC, Lara-Pezzi E, Lopez-Cabrera M, de Landazuri MO (1997) Expression of the leukocyte early activation antigen CD69 is regulated by the transcription factor AP-1. J Immunol 159(11):5463–5473

    CAS  PubMed  Google Scholar 

  29. Munro JM, Briscoe DM, Tedder TF (1996) Differential regulation of leucocyte L-selectin (CD62L) expression in normal lymphoid and inflamed extralymphoid tissues. J Clin Pathol 49(9):721–727

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Nolte MA, Kraal G, Mebius RE (2004) Effects of fluorescent and nonfluorescent tracing methods on lymphocyte migration in vivo. Cytom A 61(1):35–44

    Article  Google Scholar 

  31. Leblanc J, Fliss I, Matar C (2004) Induction of a humoral immune response following an Escherichia coli O157:H7 infection with an immunomodulatory peptidic fraction derived from Lactobacillus helveticus-fermented milk. Clin Diagn Lab Immunol 11(6):1171–1181

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Gonnella PA, Chen Y, Inobe J, Komagata Y, Quartulli M, Weiner HL (1998) In situ immune response in gut-associated lymphoid tissue (GALT) following oral antigen in TCR-transgenic mice. J Immunol 160(10):4708–4718

    CAS  PubMed  Google Scholar 

  33. Mangeney M, Lingwood CA, Taga S, Caillou B, Tursz T, Wiels J (1993) Apoptosis induced in Burkitt’s lymphoma cells via Gb3/CD77, a glycolipid antigen. Cancer Res 53(21):5314–5319

    CAS  PubMed  Google Scholar 

  34. Marcato P, Mulvey G, Armstrong GD (2002) Cloned Shiga toxin 2 B subunit induces apoptosis in Ramos Burkitt’s lymphoma B cells. Infect Immun 70(3):1279–1286

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Imai Y, Fukui T, Ikegaya A, Ishikawa T, Ono Y, Kurohane K (2002) Lack of Shiga-like toxin binding sites in germinal centres of mouse lymphoid tissues. Immunology 105(4):509–514

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Brandtzaeg P, Johansen FE (2005) Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol Rev 206:32–63

    Article  CAS  PubMed  Google Scholar 

  37. Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M (1996) A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87(6):1037–1047

    Article  CAS  PubMed  Google Scholar 

  38. Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B (1998) B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med 187(4):655–660

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102(5):553–563

    Article  CAS  PubMed  Google Scholar 

  40. Stevens SK, Weissman IL, Butcher EC (1982) Differences in the migration of B and T lymphocytes: organ-selective localization in vivo and the role of lymphocyte-endothelial cell recognition. J Immunol 128(2):844–851

    CAS  PubMed  Google Scholar 

  41. Okahashi N, Yamamoto M, Vancott JL, Chatfield SN, Roberts M, Bluethmann H, Hiroi T, Kiyono H, McGhee JR (1996) Oral immunization of interleukin-4 (IL-4) knockout mice with a recombinant Salmonella strain or cholera toxin reveals that CD4+ Th2 cells producing IL-6 and IL-10 are associated with mucosal immunoglobulin A responses. Infect Immun 64(5):1516–1525

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, Adams DH, von Andrian UH (2006) Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314(5802):1157–1160

    Article  CAS  PubMed  Google Scholar 

  43. Itoh S, Kariya M, Nagano K, Yokoyama S, Fukao T, Yamazaki Y, Mori H (2002) New rapid enzyme-linked immunosorbent assay to detect antibodies against bacterial surface antigens using filtration plates. Biol Pharm Bull 25(8):986–990

    Article  CAS  PubMed  Google Scholar 

  44. Siegler RL, Griffin PM, Barrett TJ, Strockbine NA (1993) Recurrent hemolytic uremic syndrome secondary to Escherichia coli O157:H7 infection. Pediatrics 91(3):666–668

    CAS  PubMed  Google Scholar 

  45. Naylor SW, Flockhart A, Nart P, Smith DG, Huntley J, Gally DL, Low JC (2007) Shedding of Escherichia coli O157:H7 in calves is reduced by prior colonization with the homologous strain. Appl Environ Microbiol 73(11):3765–3767

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Karmali MA, Petric M, Winkler M, Bielaszewska M, Brunton J, van de Kar N, Morooka T, Nair GB, Richardson SE, Arbus GS (1994) Enzyme-linked immunosorbent assay for detection of immunoglobulin G antibodies to Escherichia coli Vero cytotoxin 1. J Clin Microbiol 32(6):1457–1463

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Lopez EL, Diaz M, Devoto S, Grinstein S, Woloj M, Murray BE, Rubeglio E, Mendilaharzu F, Turco M, Vasquez M et al (1991) Evidence of infection with organisms producing Shiga-like toxins in household contacts of children with the hemolytic uremic syndrome. Pediatr Infect Dis J 10(1):20–24

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) Grants 417-08 and 427-11, Argentina. The authors thank Héctor Costa and Gabriela Camerano for their excellent technical assistance.

Conflict of interest

The authors have no financial conflicts of interest.

Author information

Authors and Affiliations

  1. Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Academia Nacional de Medicina, Pacheco de Melo 3081 (C1425AUM), Buenos Aires, Argentina

    Romina Jimena Fernandez-Brando, Gabriel Cabrera, María Pilar Mejías, Cecilia Analia Panek, María Jimena Abrey-Recalde, Leticia Verónica Bentancor, María Victoria Ramos & Marina Sandra Palermo

  2. Servicio de Fisiopatogenia, Instituto Nacional de Enfermedades Infecciosas-ANLIS “Dr. Carlos G. Malbrán”, Buenos Aires, Argentina

    Ariela Baschkier, Elizabeth Miliwebsky & Marta Rivas

Authors
  1. Romina Jimena Fernandez-Brando
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriel Cabrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ariela Baschkier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. María Pilar Mejías
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cecilia Analia Panek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elizabeth Miliwebsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. María Jimena Abrey-Recalde
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leticia Verónica Bentancor
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. María Victoria Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marta Rivas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marina Sandra Palermo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marina Sandra Palermo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fernandez-Brando, R.J., Cabrera, G., Baschkier, A. et al. Oral administration of Shiga toxin-producing Escherichia coli induces intestinal and systemic specific immune response in mice. Med Microbiol Immunol 203, 145–154 (2014). https://doi.org/10.1007/s00430-013-0325-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-013-0325-y

Keywords

Search

Navigation