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Clinical and Vaccine Immunology, May 2009, p. 712-718, Vol. 16, No. 5
1071-412X/09/$08.00+0     doi:10.1128/CVI.00328-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A DNA Vaccine Encoding the Enterohemorragic Escherichia coli Shiga-Like Toxin 2 A2 and B Subunits Confers Protective Immunity to Shiga Toxin Challenge in the Murine Model{triangledown}

Leticia V. Bentancor,1,2 Marcos Bilen,2 Romina J. Fernández Brando,1 María Victoria Ramos,1 Luis C. S. Ferreira,3 Pablo D. Ghiringhelli,2 and Marina S. Palermo1*

División Inmunología, Instituto de Leucemia Experimental, Instituto de Investigationes Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina,1 Laboratorio de Ingeniería Genética y Biología Celular y Molecular, Universidad Nacional de Quilmes, Buenos Aires, Argentina,2 Departamento de Microbiologia, Universidade de São Paulo, São Paulo, Brazil3

Received 11 September 2008/ Returned for modification 18 November 2008/ Accepted 8 January 2009

Production of verocytotoxin or Shiga-like toxin (Stx), particularly Stx2, is the basis of hemolytic uremic syndrome, a frequently lethal outcome for subjects infected with Stx2-producing enterohemorrhagic Escherichia coli (EHEC) strains. The toxin is formed by a single A subunit, which promotes protein synthesis inhibition in eukaryotic cells, and five B subunits, which bind to globotriaosylceramide at the surface of host cells. Host enzymes cleave the A subunit into the A1 peptide, endowed with N-glycosidase activity to the 28S rRNA, and the A2 peptide, which confers stability to the B pentamer. We report the construction of a DNA vaccine (pStx2{Delta}AB) that expresses a nontoxic Stx2 mutated form consisting of the last 32 amino acids of the A2 sequence and the complete B subunit as two nonfused polypeptides. Immunization trials carried out with the DNA vaccine in BALB/c mice, alone or in combination with another DNA vaccine encoding granulocyte-macrophage colony-stimulating factor, resulted in systemic Stx-specific antibody responses targeting both A and B subunits of the native Stx2. Moreover, anti-Stx2 antibodies raised in mice immunized with pStx2{Delta}AB showed toxin neutralization activity in vitro and, more importantly, conferred partial protection to Stx2 challenge in vivo. The present vector represents the second DNA vaccine so far reported to induce protective immunity to Stx2 and may contribute, either alone or in combination with other procedures, to the development of prophylactic or therapeutic interventions aiming to ameliorate EHEC infection-associated sequelae.

* Corresponding author. Mailing address: Lab. Inmunología (IIHema), Academia Nacional de Medicina, P. de Melo 3081 (1425), Buenos Aires, Argentina. Phone: 5411 4805 5695. Fax: 5411 4803 9475. E-mail: mspalermo{at}hematologia.anm.edu.ar

{triangledown} Published ahead of print on 28 January 2009.

Clinical and Vaccine Immunology, May 2009, p. 712-718, Vol. 16, No. 5
1071-412X/09/$08.00+0     doi:10.1128/CVI.00328-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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