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Reduction of parasite levels in blood improves pregnancy outcome during experimental Trypanosoma cruzi infection

Published online by Cambridge University Press:  14 April 2009

M. E. SOLANA*
Affiliation:
Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155. Piso 13. (1121) Buenos Aires, Argentina
C. D. ALBA SOTO
Affiliation:
Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155. Piso 13. (1121) Buenos Aires, Argentina
M. C. FERNÁNDEZ
Affiliation:
Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155. Piso 13. (1121) Buenos Aires, Argentina
C. V. PONCINI
Affiliation:
Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155. Piso 13. (1121) Buenos Aires, Argentina
M. POSTAN
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chabén’/Administración Nacional de Laboratorios e Institutos de Salud ‘Dr. Carlos G. Malbrán’ (ANLIS/Malbrán), Paseo Colón 568 (1063) Buenos Aires, Argentina
S. M. GONZÁLEZ CAPPA
Affiliation:
Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155. Piso 13. (1121) Buenos Aires, Argentina
*
*Corresponding author: Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires (CP1121) Buenos Aires, Argentina. Tel: +5411 5950 9619. Fax: +5411 5950 9577. E-mail: [email protected]

Summary

Infection with a myotropic Trypanosoma cruzi clone induces maternal fertility failure. In the current work, we evaluated whether reduction of maternal parasitaemia before mating has beneficial effects on pregnancy outcome. Female mice were subjected to benznidazole (Bz) treatment after infection. On day 30 of therapy, mating was assessed and pregnancy outcome was determined on day 14 of gestation. Fetal resorptions diminished in T. cruzi-infected Bz-treated mice compared with T. cruzi-infected untreated mice. This was in agreement with the reduction in the blood/solid tissue parasite load and with the percentage of necrotic foci in placental samples from T. cruzi-infected Bz-treated females. To study eventual changes in the immune homeostasis of T. cruzi-infected Bz-treated mice, activation of the immune system was evaluated at the end of Bz therapy and before mating. We found specific IgG1 reduction resulting in a predominance of specific IgG2a, reduced numbers of CD69+ CD4+ cells and diminished frequency and numbers of CD44+ T cells. Concanavalin A-stimulated splenocytes from T. cruzi-infected Bz-treated mice produced higher amounts of IFN-γ than T. cruzi-infected untreated mice. These results indicate that reduction of maternal parasite load improves pregnancy outcome. These findings correlate with a favourable modulation of the immune response.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2009

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References

REFERENCES

Ahmed, R. and Gray, D. (1996). Immunological memory and protective immunity: understanding their relation. Science 272, 5460. doi: 10.1126/science.272.5258.54.CrossRefGoogle ScholarPubMed
Añez, N., Carrasco, H., Parada, H., Crisante, G., Rojas, A., Fuenmayor, C., Gonzalez, N., Percoco, G., Borges, R., Guevara, P. and Ramirez, J. L. (1999). Myocardial parasite persistence in chronic chagasic patients. American Journal of Tropical Medicine and Hygiene 60, 726732.CrossRefGoogle ScholarPubMed
Bertocchi, G. L., Álvarez, M. G., Pérez, D., Armenti, A., Viotti, R. J., Lococo, B., Petti, M., Postan, M., Albareda, M. C., Laucella, S. A. and Tarleton, R. L. (2008). Evaluación inmunológica del tratamiento con benznidazol en la enfermedad de Chagas crónica. Revista Argentina de Cardiología 76, 260265.Google Scholar
Burgos, J. M., Altcheh, J., Bisio, M., Duffy, T., Valadares, H. M., Seidenstein, M. E., Piccinali, R., Freitas, J. M., Levin, M. J., Macchi, L., Macedo, A. M., Freilij, H. and Schijman, A. G. (2007). Direct molecular profiling of minicircle signatures and lineages of Trypanosoma cruzi bloodstream populations causing congenital Chagas' disease. International Journal for Parasitology 37, 13191327. doi: 10.1016/j.ijpara.2007.04.015.CrossRefGoogle ScholarPubMed
Bustamante, J. M., Bixby, L. M. and Tarleton, R. L. (2008). Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas' disease. Nature Medicine 14, 542550. doi: 10.1038/nm1744.CrossRefGoogle ScholarPubMed
Cardillo, F., Postol, E., Nihei, J., Aroeira, L. S., Nomizo, A. and Mengel, J. (2007). B cells modulate T cells so as to favour T helper type 1 and CD8+ T-cell responses in the acute phase of Trypanosoma cruzi infection. Immunology 122, 584595. doi:10.1111/J.1365-2567.2007.02677-xCrossRefGoogle Scholar
Dos Reis, G. (1997). Cell-mediated immunity in experimental Trypanosoma cruzi infection. Parasitology Today 13, 335342. doi:10.1016/S0169-4758(97)01073-9.CrossRefGoogle ScholarPubMed
Freilij, H., Muller, L. and González Cappa, S. M. (1983). Direct micromethod for diagnosis of acute and congenital Chagas' disease. Journal of Clinical Microbiology 18, 327330.CrossRefGoogle Scholar
Garcia, S., Ramos, C. O., Senra, J. F., Vilas-Boas, F., Rodrigues, M. M., Campos-de-Carvalho, A. C., Ribeiro-dos-Santos, R. and Soares, M. B. (2005). Treatment with benznidazole during the chronic phase of experimental Chagas' disease decreases cardiac alterations. Antimicrobial Agents and Chemotherapy 49, 15211528. doi: 10.1128/AAC.49.4.1521-1528.2005.CrossRefGoogle ScholarPubMed
Gazzinelli, R., Pereira, M. E., Romanha, A., Gazzinelli, G. and Brener, Z. (1991). Direct lysis of Trypanosoma cruzi: a novel effector mechanism of protection mediated by human anti-gal antibodies. Parasite Immunology 13, 345356. doi:10.1111/j.1365-3024.1991.tb00288.xCrossRefGoogle ScholarPubMed
González Cappa, S. M., Chiale, P., Del Prado, G. E., Katzin, A. M., Martín, G. W., Isola, E. L. D., Abramo Obrego, L. A. and Segura, E. L. (1980). Aislamiento de una cepa de T. cruzi de un paciente con miocardiopatía chagásica crónica y su caracterización biológica. Medicina (Buenos Aires) (Suppl. 1) 40, 6368.Google Scholar
Hernandez-Matheson, I. M., Frankowski, R. F. and Held, B. (1983). Foeto-maternal morbidity in the presence of antibodies to Trypanosoma cruzi. Transactions of the Royal Society of Tropical Medicine and Hygiene 77, 405411.CrossRefGoogle ScholarPubMed
Higo, H., Miura, S., Horio, M., Mimori, M., Hamano, S., Agatsuma, T., Yanagi, T., Cruz-Reyes, A., Uyema, N., Rojas de Arias, A., Matta, V., Akahane, H., Hirayama, K., Takeuchi, T., Tada, I. and Himeno, K. (2004). Genotypic variation among lineages of Trypanosoma cruzi and its geographic aspects. Parasitology International 53, 337344. doi:10.1016/j.parint.2004.06.001CrossRefGoogle ScholarPubMed
Kalia, V., Sarkar, S., Gourley, T. S., Rouse, B. T. and Ahmed, R. (2006). Differentiation of memory B and T cells. Current Opinion in Immunology 18, 255264. doi:10.1016/j.coi.2006.03.020.CrossRefGoogle ScholarPubMed
Krautz, G. M., Kissinger, J. C. and Krettli, A. U. (2000). The targets of the lytic antibody response against Trypanosoma cruzi. Parasitology Today 16, 3134. doi:10.1016/S0169-4758(99)01581-1.CrossRefGoogle ScholarPubMed
Marcet, P. L., Duffy, T., Cardinal, M. V., Burgos, J. M., Lauricella, M. A., Levin, M. J., Kitron, U., Gürtler, R. E. and Schijman, A. G. (2006). PCR-based screening and lineage identification of Trypanosoma cruzi directly from faecal samples of triatomine bugs from northwestern Argentina. Parasitology 132, 5765. doi:10.1017/S0031182005008772.CrossRefGoogle ScholarPubMed
Marinho, C. R., D'Imperio Lima, M. R., Grisotto, M. G. and Alvarez, J. M. (1999). Influence of acute-phase parasite load on pathology, parasitism, and activation of the immune system at the late chronic phase of Chagas' disease. Infection and Immunity 67, 308318.CrossRefGoogle ScholarPubMed
Marinho, C. R. F., Nuñez-Apaza, L. N., Martins-Santos, R., Bastos, K. R. B., Bombeiro, A. L., Bucci, D. Z., Sardinha, L. R., Lima, M. R. D. and Álvarez, J. M. (2007). IFN-γ, but not nitric oxide or specific IgG, is essential for the in vivo control of low-virulence Sylvio X10/4 Trypanosoma cruzi parasites. Scandinavian Journal of Immunology 66, 297308. doi:10.1111/j.1365-3083.2007.01958.xCrossRefGoogle ScholarPubMed
Marin-Neto, J. A., Cunha-Neto, E., Maciel, B. C. and Simões, M. V. (2007). Pathogenesis of Chronic Chagas Heart Disease. Circulation 115, 11091123. doi: 10.1161/CIRCULATIONAHA.106.624296.CrossRefGoogle ScholarPubMed
Martins-Filho, O., Pereira, M. E. S., Carvalho, J. F., Cançado, J. R. and Brener, Z. (1995). Flow cytometry, a new approach to detect anti-live trypomastigote antibodies and monitor the efficacy of specific treatment in human Chagas' disease. Clinical and Diagnostic Laboratory Immunology 2, 569573.CrossRefGoogle ScholarPubMed
Martins-Filho, O. A., Eloi-Santos, S. M., Teixeira Carvalho, A., Oliveira, R. C., Rassi, A., Luquetti, A. O., Rassi, G. G. and Brener, Z. (2002). Double-blind study to evaluate flow cytometry analysis of anti-live trypomastigote antibodies for monitoring treatment efficacy in cases of human Chagas' disease. Clinical and Diagnostic Laboratory Immunology 9, 11071113. doi: 10.1128/CDLI.9.5.1107-1113.2002.Google ScholarPubMed
Maya, J. D., Cassels, B. K., Iturriaga-Vásquez, P., Ferreira, J., Faúndez, M., Galanti, N., Ferreira, A. and Morello, A. (2007). Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comparative Biochemistry and Physiology 146, 601620. doi:10.1016/j.cbpa.2006.03.004.CrossRefGoogle ScholarPubMed
Michailowsky, V., Murta, S. M. F., Carvalho-Oliveira, L., Pereira, M. E., Ferreira, L. R., Brener, Z., Romanha, A. J. and Gazzinelli, R. T. (1998). Interleukin-12 enhances in vivo parasiticidal effect of benznidazole during acute experimental infection with a naturally drug-resistant strain of Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 42, 25492556.CrossRefGoogle ScholarPubMed
Mirkin, G.A, Celentano, A. M., Malchiodi, E. L., Jones, M. and González Cappa, S. M. (1997). Different Trypanosoma cruzi strains promote neuromyopathic damage mediated by distinct T lymphocyte subsets. Clinical and Experimental Immunology 107, 328334. doi: 10.1111/j.1365-2249.1997.267-ce1166.x.CrossRefGoogle ScholarPubMed
Mjihdi, A., Lambot, M. A., Stewart, I. J., Detournay, O., Noël, J. C., Carlier, Y. and Truyens, C. (2002). Acute Trypanosoma cruzi infection in mouse induces infertility or placental parasite invasion and ischemic necrosis associated with massive fetal loss. American Journal of Pathology 161, 673680.CrossRefGoogle ScholarPubMed
Murta, S. M., Ropert, C., Alves, R. O., Gazzinelli, R. T. and Romanha, A. J. (1999). In-vivo treatment with benznidazole enhances phagocytosis, parasite destruction and cytokine release by macrophages during infection with a drug-susceptible but not with a derived drug-resistant Trypansoma cruzi population. Parasite Immunology 21, 535544. doi: 10.1046/j.1365-3024.1999.00251.xCrossRefGoogle Scholar
Olivieri, B. P., Cotta-De-Almeida, V. and Araújo-Jorge, T. (2002). Benznidazole treatment following acute Trypanosoma cruzi infection triggers CD8+ T-cell expansion and promotes resistance to reinfection. Antimicrobial Agents and Chemotherapy 46, 37903796. doi: 10.1128/AAC.46.12.3790-3796.2002.CrossRefGoogle ScholarPubMed
Piaggio, E., Roggero, E., Pitashny, M., Wietzerbin, J., Bottasso, O. A. and Revelli, S. S. (2001). Treatment with benznidazole and its immunomodulating effects on Trypanosoma cruzi-infected rats. Parasitology Research 87, 539547. doi: 10.1007/s004360000357.Google ScholarPubMed
Risso, M. G., Garbarino, G. B., Mocetti, E, Campetella, O., Gonzalez Cappa, S. M., Buscaglia, C. A. and Leguizamon, M. S. (2004). Differential expression of a virulence factor, the trans-sialidase, by the main Trypanosoma cruzi phylogenetic lineages. Journal of Infectious Diseases 189, 22502259. doi: 10.1086/420831.CrossRefGoogle ScholarPubMed
Rodriguez, A. M., Santero, F., Afchain, D., Bazin, H. and Capron, A. (1981). Trypanosoma cruzi infection in B-cell-deficient rats. Infection and Immunity 31, 524529.CrossRefGoogle ScholarPubMed
Romanha, A. J., Alves, R. O., Murta, S. M., Silva, J. S., Ropert, C. and Gazzinelli, R. T. (2002). Experimental chemotherapy against Trypanosoma cruzi infection: essential role of endogenous interferon-γ in mediating parasitologic cure. Journal of Infectious Diseases 186, 823828. doi: 10.1086/342415CrossRefGoogle ScholarPubMed
Rozas, M., Botto-Mahan, C., Coronado, X., Ortiz, S., Cattan, P. E. and Solari, A. (2007). Coexistence of Trypanosoma cruzi genotypes in wild and periodomestic mammals in Chile. American Journal of Tropical Medicine and Hygiene 77, 647653.CrossRefGoogle ScholarPubMed
Sathler-Avelar, R., Vitelli-Avelar, D. M., Lima Massara, R., de Lana, M., Pinto Dias, J. C., Teixeira-Carvalho, A., Eloi-Santos, S. M. and Martins-Filho, O. A. (2008). Etiological treatment during early chronic indeterminate Chagas disease incites an activated status on innate and adaptive immunity associated with a type 1-modulated cytokine pattern. Microbes and Infection 10, 103113. doi:10.1016/j.micinf.2007.10.009CrossRefGoogle ScholarPubMed
Sathler-Avelar, R., Vitelli-Avelar, D. M., Massara, R. L., Borges, J. D., Lana, M., Teixeira-Carvalho, A., Dias, J. C., Elói-Santos, S. M. and Martins-Filho, O. A. (2006). Benznidazole treatment during early-indeterminate Chagas' disease shifted the cytokine expression by innate and adaptive immunity cells toward a type 1-modulated immune profile. Scandinavian Journal of Immunology 64, 554563. doi: 10.1111/j.1365-3083.2006.01843.xCrossRefGoogle Scholar
Savino, W., Villa-Verde, D., Mendes-da-Cruz, D., Silva-Monteiro, E., Perez, A., Aoki, M. P., Bottasso, O., Guiñazú, N., Silva-Barbosa, S. and Gea, S. (2007). Cytokines and cell adhesion receptors in the regulation of immunity to Trypanosoma cruzi. Cytokine & Growth Factor Reviews 18, 107124. doi:10.1016/j.cytogfr.2007.01.010.CrossRefGoogle ScholarPubMed
Solana, M. E., Celentano, A. M., Tekiel, V. S., Jones, M. and González Cappa, S. M. (2002). Trypanosoma cruzi: effect of parasite subpopulations on murine pregnancy outcome. Journal of Parasitology 88, 102106.CrossRefGoogle ScholarPubMed
Steindel, M., Kramer Pacheco, L., Scholl, D., Soares, M., de Moraes, M. H., Eger, I., Kosmann, C., Sincero, T. C., Stoco, P. H., Murta, S. M., de Carvalho-Pinto, C. J. and Grisard, E. C. (2008). Characterization of Trypanosoma cruzi isolated from humans, vectors, and animal reservoirs following an outbreak of acute human Chagas disease in Santa Catarina State, Brazil. Diagnostic Microbiology and Infectious Disease 60, 2532. doi:10.1016/j.diagmicrobio.2007.07.016.CrossRefGoogle ScholarPubMed
Sztein, M. B. and Kierszenbaum, F. (1992). Suppression by Trypanosoma cruzi of T-cell receptor expression by activated human lymphocytes. Immunology 77, 277283.Google ScholarPubMed
Tarleton, R. L. (2001). Parasite persistence in the aetiology of Chagas disease. International Journal for Parasitology 31, 549553. doi:10.1016/S0020-7519(01)00158-8.CrossRefGoogle ScholarPubMed
Torrico, M. C., Solano, M., Guzmán, J. M., Parrado, R., Suarez, E., Alonzo-Vega, C., Truyens, C., Carlier, Y. and Torrico, F. (2005). Estimation of the parasitaemia in Trypanosoma cruzi human infection: high parasitaemias are associated with severe and fatal congenital Chagas disease. Revista da Sociedade Brasileira de Medicina Tropical 38 (Suppl. 2), 5861.Google ScholarPubMed
Viotti, R., Vigliano, C., Lococo, B., Bertocchi, G., Petti, M., Alvarez, M. G., Postan, M. and Armenti, A. (2006). Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Annals of Internal Medicine 144, 724734.CrossRefGoogle ScholarPubMed
Virreira, M., Serrano, G., Maldonado, L. and Svoboda, M. (2006). Trypanosoma cruzi: typing of genotype (sub)lineages in megacolon samples from bolivian patients. Acta Tropica 100, 252255. doi:10.1016/j.actatropica.2006.11.005CrossRefGoogle ScholarPubMed
Virreira, M., Truyens, C., Alonso-Vega, C., Brutus, L., Jijena, J., Torrico, F., Carlier, Y. and Svoboda, M. (2007). Comparison of Trypanosoma cruzi lineages and levels of parasitic DNA in infected mothers and their newborns. American Journal of Tropical Medicine and Hygiene 77, 102106.CrossRefGoogle ScholarPubMed
Vitelli-Avelar, D. M., Sathler-Avelar, R., Wendling, A. P., Rocha, R. D., Teixeira-Carvalho, A., Martins, N. E., Dias, J. C., Rassi, A., Luquetti, A. O., Elói-Santos, S. M. and Martins-Filho, O. A. (2007). Non-conventional flow cytometry approaches to detect anti-Trypanosoma cruzi immunoglobulin G in the clinical laboratory. Journal of Immunological Methods 318, 102112. doi:10.1016/j.jim.2006.10.009.CrossRefGoogle ScholarPubMed
World Health Organization (2002). Control of Chagas disease. WHO Technical Report Series No. 905. World Health Organization, Geneva, Switzerland.Google Scholar
Zhang, L. and Tarleton, R. L. (1999). Parasite persistence correlates with disease severity and localization in chronic Chagas' disease. Journal of Infectious Diseases 180, 480486. doi: 10.1086/314889.CrossRefGoogle ScholarPubMed