RESUMO
Chagas disease by Trypanosoma cruzi (T. cruzi) infection is a leading cause of myocarditis worldwide. Chagas cardiomyopathy is presented with a wide variety of conduction abnormalities including arrhythmias, first- and second-degree atrioventricular blockade, left ventricular systolic dysfunction and some cases heart failure leading to the death. Currently, there are no effective treatments available against advanced Chagas disease. With the advance in the development of novel therapies, it is important to utilize an animal model that can effectively replicate the diverse stages of Chagas disease, including chronic asymptomatic and symptomatic infection, that are akin to those observed in humans. Therefore, to characterize the cardiac alterations during the evolution of the infection, we evaluated the progression of cardiomyopathy caused by T. cruzi H1 infection in both BALB/c and ICR mouse models by performing electrocardiogram (ECG) studies in unanesthetized mice every month until 210 days post-infection (dpi). In the late chronic phase of infection, we also performed echocardiogram (ECHO) studies to further assess cardiac function. In conclusion, we demonstrated that ICR mice were more susceptible to cardiac alterations compared to BALB/c mice and both mouse strains are suitable experimental models to study chronic T. cruzi infection and novel treatments.
Assuntos
Cardiomiopatia Chagásica , Doença de Chagas , Trypanosoma cruzi , Humanos , Animais , Camundongos , Infecção Persistente , Camundongos Endogâmicos ICR , CoraçãoRESUMO
BACKGROUND: Chagas disease (CD) is caused by Trypanosoma cruzi and affects 6-7 million people worldwide. Approximately 30% of chronic patients develop chronic chagasic cardiomyopathy (CCC) after decades. Benznidazole (BNZ), one of the first-line chemotherapy used for CD, induces toxicity and fails to halt the progression of CCC in chronic patients. The recombinant parasite-derived antigens, including Tc24, Tc24-C4, TSA-1, and TSA-1-C4 with Toll-like receptor 4 (TLR-4) agonist-adjuvants reduce cardiac parasite burdens, heart inflammation, and fibrosis, leading us to envision their use as immunotherapy together with BNZ. Given genetic immunization (DNA vaccines) encoding Tc24 and TSA-1 induce protective immunity in mice and dogs, we propose that immunization with the corresponding recombinant proteins offers an alternative and feasible strategy to develop these antigens as a bivalent human vaccine. We hypothesized that a low dose of BNZ in combination with a therapeutic vaccine (TSA-1-C4 and Tc24-C4 antigens formulated with a synthetic TLR-4 agonist-adjuvant, E6020-SE) given during early chronic infection, could prevent cardiac disease progression and provide antigen-specific T cell immunity. METHODOLOGY/ PRINCIPAL FINDINGS: We evaluated the therapeutic vaccine candidate plus BNZ (25 mg/kg/day/7 days) given on days 72 and 79 post-infection (p.i) (early chronic phase). Fibrosis, inflammation, and parasite burden were quantified in heart tissue at day 200 p.i. (late chronic phase). Further, spleen cells were collected to evaluate antigen-specific CD4+ and CD8+ T cell immune response, using flow cytometry. We found that vaccine-linked BNZ treated mice had lower cardiac fibrosis compared to the infected untreated control group. Moreover, cells from mice that received the immunotherapy had higher stimulation index of antigen-specific CD8+Perforin+ T cells as well as antigen-specific central memory T cells compared to the infected untreated control. CONCLUSIONS: Our results suggest that the bivalent immunotherapy together with BNZ treatment given during early chronic infection protects BALB/c mice against cardiac fibrosis progression and activates a strong CD8+ T cell response by in vitro restimulation, evidencing the induction of a long-lasting T. cruzi-immunity.
Assuntos
Doença de Chagas , Vacinas Protozoárias , Trypanosoma cruzi , Vacinas de DNA , Adjuvantes Imunológicos , Animais , Doença de Chagas/tratamento farmacológico , Cães , Fibrose , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Nitroimidazóis , Perforina , Proteínas Recombinantes , Receptor 4 Toll-Like , Trypanosoma cruzi/genética , Vacinas Combinadas/uso terapêuticoRESUMO
More than 110 years after Chagas disease discovery, some aspects of the mechanisms involved in the physiopathology of heart damage are still unknown. Previously, Trypanosoma cruzi was considered to be the only cause of myocardial injury. Currently, there are other known mechanisms involved in the physiopathology of Chagas heart disease, including the immune-inflammatory response, autoimmunity, microvascular abnormalities and nerve damage, which are interrelated and contribute to cardiac damage. Nowadays, the parasite is the main cause of cardiac damage during the acute stage of Chagas disease and the one that initiates the complex physiopathological network that triggers the other mentioned mechanisms. The consequence of these pathophysiological mechanisms is progressive deterioration of cardiac function that ultimately establishes Chronic Chagasic cardiomyopathy. The aim of this review is to describe and discuss the main physiopathological mechanisms that are currently being postulated with respect to cardiac damage in T. cruzi infection.
A más de 110 años del descubrimiento de la enfermedad de Chagas, aún se desconocen aspectos sobre los mecanismos implicados en la fisiopatología del daño cardiaco. Anteriormente se consideraba al Trypanosoma cruzi como el único causante de la lesión en el miocardio. Ahora se conocen otros mecanismos implicados en la fisiopatología, como la respuesta inmunitaria-inflamatoria, la autoinmunidad, las anomalías microvasculares y el daño nervioso, los cuales se encuentran interrelacionados para contribuir en el daño cardiaco. En la actualidad se reconoce al parásito como el principal causante del daño durante la etapa aguda y el que inicia la compleja red fisiopatológica que desencadena los otros mecanismos mencionados. El resultado de todos estos mecanismos fisiopatológicos es el deterioro progresivo de la función cardiaca, lo cual termina por establecer la cardiomiopatía chagásica crónica. El propósito de esta revisión es describir y discutir los principales mecanismos fisiopatológicos que se postulan con respecto al daño cardiaco en la infección por T. cruzi.
Assuntos
Cardiomiopatia Chagásica , Trypanosoma cruzi , Cardiomiopatia Chagásica/diagnóstico , HumanosRESUMO
BACKGROUND: Cutaneous leishmaniasis is a tropical disease affecting over one million patients annually and Leishmania (L.) mexicana is one of the major etiological agents in the Americas. Here we established the first experimental infection of L. (L.) mexicana in canids. METHODS: Beagle dogs were infected intradermally with culture-derived L. (L.) mexicana. We followed skin ulcer development, histopathological signs, parasite burden and the immune status of the infected dogs. RESULTS: All infected dogs developed uniform oval-craterform ulcers similar to those observed in humans, associated with mixed T helper 1/T helper 2 immune responses. Parasites were detected in the healed lesions 15 weeks post-infection. Higher anti-Leishmania IgG levels correlated with larger lesions and high IgG1/IgG2 ratio was associated with some level of splenomegaly. CONCLUSIONS: The canine model described in this work will be of use for further understanding of L. (L.) mexicana immunopathogenensis, and for drug and vaccine development.