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Infection and Immunity, January 2008, p. 324-333, Vol. 76, No. 1
0019-9567/08/$08.00+0     doi:10.1128/IAI.01163-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Oral Vaccination with Salmonella enterica as a Cruzipain-DNA Delivery System Confers Protective Immunity against Trypanosoma cruzi{triangledown}

Silvia I. Cazorla,1,2 Pablo D. Becker,3 Fernanda M. Frank,1,2 Thomas Ebensen,3 María J. Sartori,4 Ricardo S. Corral,5 Emilio L. Malchiodi,1,2* and Carlos A. Guzmán3*

Cátedra de Inmunología and Instituto de Estudios de la Inmunidad Humoral, CONICET-UBA, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina,1 Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina,2 Department of Vaccinology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany,3 Instituto de Biología Celular, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina,4 Laboratorio de Virología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina5

Received 21 August 2007/ Returned for modification 22 September 2007/ Accepted 21 October 2007

To stimulate both local and systemic immune responses against Trypanosoma cruzi, Salmonella enterica serovar Typhimurium aroA was exploited as a DNA delivery system for cruzipain (SCz). In a murine model we compared SCz alone (GI) or coadministered with Salmonella carrying a plasmid encoding granulocyte-macrophage colony-stimulating factor (GII), as well as protocols in which SCz priming was followed by boosting with recombinant cruzipain (rCz) admixed with either CpG-ODN (GIII) or MALP-2, a synthetic derivative of a macrophage-activating lipopeptide of 2 kDa from Mycoplasma fermentans (GIV). The results showed that protocols that included four oral doses of SCz (GI) elicited mainly a mucosal response characterized by immunoglobulin A (IgA) secretion and proliferation of gut-associated lymphoid tissue cells, with weak systemic responses. In contrast, the protocol that included a boost with rCz plus CpG (GIII) triggered stronger systemic responses in terms of Cz-specific serum IgG titers, splenocyte proliferation, gamma interferon (IFN-{gamma}) secretion, and delayed-type hypersensitivity response. Trypomastigote challenge of vaccinated mice resulted in significantly lower levels of parasitemia compared to controls. Protection was abolished by depletion of either CD4+ or CD8+ T cells. Parasite control was also evident from the reduction of tissue damage, as revealed by histopathologic studies and serum levels of enzymes that are markers of muscle injury in chronic Chagas' disease (i.e., creatine kinase, aspartate aminotransferase, and lactate dehydrogenase). Enhanced release of IFN-{gamma} and interleukin-2 was observed in GI and GII upon restimulation of splenocytes in the nonparasitic phase of infection. Our results indicate that Salmonella-mediated delivery of Cz-DNA by itself promotes the elicitation of an immune response that controls T. cruzi infection, thereby reducing parasite loads and subsequent damage to muscle tissues.

* Corresponding author. Mailing address for Emilio L. Malchiodi: Cátedra de Inmunología and Instituto de Estudios de la Inmunidad Humoral, CONICET-UBA, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina. Phone: 5411 4964 8259. Fax: 5411 4964 0024. E-mail: emalchio{at}ffyb.uba.ar. Mailing address for Carlos A. Guzmán: Department of Vaccinology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany. Phone: 49 531 6181 4600. Fax: 49 531 6181 4699. E-mail: carlos.guzman{at}helmholtz-hzi.de

{triangledown} Published ahead of print on 29 October 2007.

Editor: W. A. Petri, Jr.

Infection and Immunity, January 2008, p. 324-333, Vol. 76, No. 1
0019-9567/08/$08.00+0     doi:10.1128/IAI.01163-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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