Benznidazole Therapy Modulates Interferon-γ and M2 Muscarinic Receptor Autoantibody Responses in Trypanosoma cruzi-Infected Children

OBJECTIVE: The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs) as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benzonidazole (BZ) could modify both response patterns. METHODS: This study comprised 30 T. cruzi-infected children (mean age: 13.8 years) and 19 uninfected controls (mean age: 12.7 years). Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. RESULTS: At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs(+) patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7-88.1% decrease at T2. IFN-γ circulating levels also declined by T2. CONCLUSION: Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses

Benznidazole therapy modulates Interferon-γ and M2 Muscarinic receptor autoantibody responses in Trypanosoma cruzi-Infected children

Fil: Cutrullis, Romina A. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Moscatelli, Guillermo F. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Moroni, Samanta. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Volta, Bibiana J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología Dr. Mario Fatala Chaben; Argentina.Fil: Cardoni, Rita L. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología Dr. Mario Fatala Chaben; Argentina.Fil: Altcheh, Jaime. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Corral, Ricardo S. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Freilij, Héctor. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Petray, Patricia B. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Objective The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs) as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benznidazole (BZ) could modify both response patterns. Methods This study comprised 30 T. cruzi-infected children (mean age: 13.8 years) and 19 uninfected controls (mean age: 12.7 years). Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. Results At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs+ patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7–88.1% decrease at T2. IFN-γ circulating levels also declined by T2. Conclusion Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses

Benznidazole therapy modulates Interferon-γ and M2 Muscarinic receptor autoantibody responses in Trypanosoma cruzi-Infected children

Fil: Cutrullis, Romina A. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Moscatelli, Guillermo F. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Moroni, Samanta. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Volta, Bibiana J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología Dr. Mario Fatala Chaben; Argentina.Fil: Cardoni, Rita L. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología Dr. Mario Fatala Chaben; Argentina.Fil: Altcheh, Jaime. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Corral, Ricardo S. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Freilij, Héctor. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Petray, Patricia B. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Objective The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs) as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benznidazole (BZ) could modify both response patterns. Methods This study comprised 30 T. cruzi-infected children (mean age: 13.8 years) and 19 uninfected controls (mean age: 12.7 years). Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. Results At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs+ patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7–88.1% decrease at T2. IFN-γ circulating levels also declined by T2. Conclusion Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses

Anti-M2R AAb and IFN-γ profiles in pediatric chagasic patients at T0 and uninfected controls.

<p>(A) Distribution of anti-M2R AAb in sera. The group mean and the standard error of the mean are depicted. Dotted line shows cut-off level of the assay. (B) Circulating levels of IFN-γ. The group mean and the standard error of the mean are depicted. * <i>p</i> = 0.015 compared to uninfected controls.</p

Distribution of IFN-γ values for <i>T. cruzi</i>-infected and uninfected children.

<p>P25: 25^th percentile. P75: 75^th percentile. * <i>p</i><0.05, T2 <i>vs</i> T0.</p

Trypanosoma cruzi discrete typing units in Chagas disease patients from endemic and non-endemic regions of Argentina

Fil: Cura, C I. Laboratorio de Biología Molecular de la Enfermedad de Chagas, Instituto de Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Vuelta de Obligado 2490, 2do piso, 1428, Ciudad de Buenos Aires; Argentina.Fil: Lucero, Raúl Horacio. Instituto de Medicina Regional, Universidad Nacional del Nordeste, Av. Las Heras 727, 3500, Resistencia, Chaco; Argentina.Fil: Bisio, Margarita. Laboratorio de Biología Molecular de la Enfermedad de Chagas, Instituto de Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Vuelta de Obligado 2490, 2do piso, 1428, Ciudad de Buenos Aires; Argentina.Fil: Oshiro, E. ANLIS Dr.C.G.Malbrán. Centro Nacional de Diagnóstico e Investigación en Endemo-Epidemias; Argentina.Fil: Formichelli, L B. Instituto de Medicina Regional, Universidad Nacional del Nordeste, Av. Las Heras 727, 3500, Resistencia, Chaco; Argentina.Fil: Burgos, Juan M. Departamento de Microbiología, Inmunología y Parasitología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121, Ciudad de Buenos Aires; Argentina.Fil: Sergio, Lejona. Área de Biología Molecular, Centro de Especialidades Médicas Ambulatorias (CEMAR), San Luis 2020, 2000, Rosario, Santa Fe; Argentina.Fil: Brusés, B L. Instituto de Medicina Regional, Universidad Nacional del Nordeste, Av. Las Heras 727, 3500, Resistencia, Chaco; Argentina.Fil: Hernández, D. Consultorio de Chagas, Facultad de Medicina, Universidad Nacional del Nordeste, Moreno 1240, 3400, Corrientes; Argentina.Fil: Severini, G V. Consultorio de Chagas, Facultad de Medicina, Universidad Nacional del Nordeste, Moreno 1240, 3400, Corrientes; Argentina.Fil: Velazquez, Elsa. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Duffy, Tomas. Laboratorio de Biología Molecular de la Enfermedad de Chagas, Instituto de Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Vuelta de Obligado 2490, 2do piso, 1428, Ciudad de Buenos Aires; Argentina.Fil: Anchart, E. Área de Biología Molecular, Centro de Especialidades Médicas Ambulatorias (CEMAR), San Luis 2020, 2000, Rosario, Santa Fe; Argentina.Fil: Lattes, R. Instituto de Nefrología, Cabello 3889, 1425, Ciudad de Buenos Aires; Argentina.Fil: Altcheh, J. Servicio de Parasitología y Enfermedad de Chagas, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, 1425, Buenos Aires; Argentina.Fil: Freilij, H. Servicio de Parasitología y Enfermedad de Chagas, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, 1425, Buenos Aires; Argentina.Fil: Diez, M. Unidad de Trasplante Cardíaco, Hospital Universitario Fundación Favaloro, Av. Belgrano 1746, 1093, Ciudad de Buenos Aires; Argentina.Fil: Nagel, C. Unidad de Trasplante Cardíaco, Hospital Universitario Fundación Favaloro, Av. Belgrano 1746, 1093, Ciudad de Buenos Aires; Argentina.Fil: Vigliano, Carlos. Unidad de Trasplante Cardíaco, Hospital Universitario Fundación Favaloro, Av. Belgrano 1746, 1093, Ciudad de Buenos Aires; Argentina.Fil: Favaloro, Liliana E. Unidad de Trasplante Cardíaco, Hospital Universitario Fundación Favaloro, Av. Belgrano 1746, 1093, Ciudad de Buenos Aires; Argentina.Fil: Favaloro, R R. Unidad de Trasplante Cardíaco, Hospital Universitario Fundación Favaloro, Av. Belgrano 1746, 1093, Ciudad de Buenos Aires; Argentina.Fil: Merino, D E. Instituto de Medicina Regional, Universidad Nacional del Nordeste, Av. Las Heras 727, 3500, Resistencia, Chaco; Argentina.Fil: Sosa-Estani, Sergio. ANLIS Dr.C.G.Malbrán. Centro Nacional de Diagnóstico e Investigación en Endemo-Epidemias; Argentina.Fil: Schijman, A G. Laboratorio de Biología Molecular de la Enfermedad de Chagas, Instituto de Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Vuelta de Obligado 2490, 2do piso, 1428, Ciudad de Buenos Aires; Argentina.Genetic diversity of Trypanosoma cruzi may play a role in pathogenesis of Chagas disease forms. Natural populations are classified into 6 Discrete Typing Units (DTUs) Tc I-VI with taxonomical status. This study aimed to identify T. cruzi DTUs in bloodstream and tissue samples of Argentinean patients with Chagas disease. PCR-based strategies allowed DTU identification in 256 clinical samples from 239 Argentinean patients. Tc V prevailed in blood from both asymptomatic and symptomatic cases and Tc I was more frequent in bloodstream, cardiac tissues and chagoma samples from immunosuppressed patients. Tc II and VI were identified in a minority of cases, while Tc III and Tc IV were not detected in the studied population. Interestingly, Tc I and Tc II/VI sequences were amplified from the same skin biopsy slice from a kidney transplant patient suffering Chagas disease reactivation. Further data also revealed the occurrence of mixed DTU populations in the human chronic infection. In conclusion, our findings provide evidence of the complexity of the dynamics of T. cruzi diversity in the natural history of human Chagas disease and allege the pathogenic role of DTUs I, II, V and VI in the studied population