Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways

Abstract\ud \ud Background\ud Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage.\ud \ud \ud Methods\ud Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.\ud \ud \ud Results\ud The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.\ud \ud \ud Conclusions\ud Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.FAPES

2 nd Brazilian Consensus on Chagas Disease, 2015

Abstract Chagas disease is a neglected chronic condition with a high burden of morbidity and mortality. It has considerable psychological, social, and economic impacts. The disease represents a significant public health issue in Brazil, with different regional patterns. This document presents the evidence that resulted in the Brazilian Consensus on Chagas Disease. The objective was to review and standardize strategies for diagnosis, treatment, prevention, and control of Chagas disease in the country, based on the available scientific evidence. The consensus is based on the articulation and strategic contribution of renowned Brazilian experts with knowledge and experience on various aspects of the disease. It is the result of a close collaboration between the Brazilian Society of Tropical Medicine and the Ministry of Health. It is hoped that this document will strengthen the development of integrated actions against Chagas disease in the country, focusing on epidemiology, management, comprehensive care (including families and communities), communication, information, education, and research

Platelet aggregation on chronic Chagas\' disease and it\'s relevance on public health

O objetivo deste estudo foi avaliar o comportamento da agregação plaquetária na fase crônica da doença de Chagas e sua relevância em Saúde Pública. Foram analisados 75 chagásicos crônicos, jovens (39 ± 6,78 anos), 48% de masculinos, 81,30% brancos, 18,70% negros. Em 61,34% não havia cardiopatia, 37,33% eram cardiopatas e 1,33% apresentavam a forma cárdio-digestiva. Todos eram assintomáticos, sem fatores de riscos aterosclerótico, exceto tabagismo, presente em 20%. O índice de agregação plaquetária médio (iapm) (Manrique 1980: 50 ·- 140 = normoagregante; 141 - 240 = hiperagregante moderado; 241 - 400 = hiperagregante severo) era 221 ± 65,65, sendo aumentado em 88% dos casos e acima de 241 em 30% deles. Em 28 pacientes hiperagregantes (236,85 ± 61,46), usou-se aspirina (100mg/dia); durante seu uso, o iapm foi 139,57±38,72 (p= 0,000). Suspensa medicação este índice voltou aos valores prévios. Utilizou-se Benzonidazol, 5mg/Kg/dia por 60 dias em 32 hiperagregantes, com iapm de 211,84 ± 53,41, que, após 6,78 + 4,20 meses da suspensão da droga, foi de 163,87+61,81 (p= 0,004). Foram obtidas as seguintes conclusões: 1.Na doença de Chagas crônica há alta prevalência de hiperagregação plaquetária. 2.Com Benznidazol, o iapm diminui significativa e permanentemente, até 6 meses depois de sua suspensão.This study was made to evaluate the platelet aggregation behavior on chronic Chagas\' disease and it\'s relevance on Public Health. We observed 75 young patients (39 ± 6,78 years) with chronic Chagas\'disease, 48% male, 81,30% white, 18,70 black. There were 61,34% without cardiopathy, 37,33% with heart disease and 1,33% with cardio and digestive condition. All were asymptomatic and there were no risk factors to atherosclerosis, except cigarette smoking (20%). The platelet aggregation rate average (P.A.R.A.) (Manrique 1980: 50- 140 =normal; 141 - 240 = moderate hyperaggregation; 241 - 400 = severe hyperaggregation) were 221±65,65. It was high in 88% of patients and over 241 in 30% of them. Twenty-eight patients presenting hyperaggregation (236,85 ± 61,46) used acetylsalicylic acid (A.S.A.) (100mg/day) and the P.A.R.A. became 139,57 + 38,72 (p = 0.000). When they stopped the drug, the index returned to former baseline. Thirty-two patients presenting hyperaggregation (211,84±53,41) used Benzonidazole (Smg/Kg/day/60 days). After 6,78 ± 4,20 months without drug the P.A.R.A. were 163,87±61,81 (p = 0.004). Conclusion: 1. On chronic Chagas\' disease there is high prevalence of platelet\'s hyperaggregation. 2. With Benzonidazole the P.A.R.A. decreases significantly and permanently, till 6 months it was stopped

Ethiological treatment of acute and chronic Chagas' heart disease

The uncertaintties in the ethiological treatment of Chagas' Disease are consequence of the lack of entire knowledge of its pathogeny and the no existence of a healing criterium. There is a consensus that antiparasite drugs should be used in the acute phase of the infection, regardless of the infection route, in new crisis, in patients under immunossuppression and in organs transplantation. There is still controversy regarding subacute, chronic or indetermined phase or cases with mild cardiac/digestive forms, not included in the situations listed above neither in a research protocol. The treatment includes oral benzonidazol 5 mg/kg/day, bid or tid for 60 days. In 71 patients monitored in this fashion, the authors have found 60% of negative xenodiagnostic at the end of treatment. It is still necessary, however, to continue to investigate and accomplishing more randomized trials to confirm the efficacy of such method, and also to try to obtain effective and less toxic agents. It is also fundamental to standardize a more reliable healing criterium

Exploring the Evolutionary Origin and Biological Role of the <em>Trypanosoma cruzi</em> Ecotin-Like Molecule in Chagas’ Disease

Enzymes called proteases play important roles in the physiology of all living organisms and in the interaction of a parasite/symbiont with its host. Different types of peptidases act on specific substrates and are regulated by specific inhibitors. Ecotins, described firstly in Eschericchia coli, are inhibitors of serine peptidases (ISP) from S1A family including trypsin, chymotrypsin, neutrophil elastase, and cathepsin G. Ecotin-like inhibitors are present in parasites from Trypanosomatidae family, including Trypanosoma cruzi, the causative agent of Chagas’ disease. This chapter explores the evolutive origin of the T. cruzi TcISP2 and its possible interactions with proteins of the human immune system and in Chagas’ disease. The phylogenetic relationship of TcISP2 with trypanosomatids ISPs, comparative loci analysis among trypanosomatids, and the occurrence of bacteria endosymbionts in the group strongly suggest horizontal transfer as the main origin mechanism for trypanosomatids ISPs, followed by duplication events and losses that could explain its current genomic pattern. The relationship of TcISP2 with the vertebrate host immune system can be inferred by its antigenicity in Chaga’s disease murine model, presenting high antibody titer after 60 days post-infection, which could indicate the inhibition of TcISP2 activity associated with chronic phase of the Chaga’s disease

Corrigendum: Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy

International audienc

Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy

International audienceChagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is the most important clinical consequence of T. cruzi infection, while the others remain asymptomatic (ASY). IFN-γ and IFN-γ-producing Th1-type T cells are increased in peripheral blood and CCC myocardium as compared to ASY patients, while the Th1-antagonizing cytokine IL-10 is more expressed in ASY patients. Importantly IFN-γ-producing Th1-type T cells are the most frequent cytokine-producing T cell subset in CCC myocardium, while expression of Th1-antagonizing cytokines IL-10 and IL-4 is unaltered. The control of IFN-γ production by Th1-type T cells may be a key event for progression toward CCC. A genetic component to disease progression was suggested by the familial aggregation of cases and the association of gene polymorphisms with CCC development. We here investigate the role of gene polymorphisms (SNPs) in several genes involved in the control of IFN-γ production and Th1 T cell differentiation in CCC development

Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.

International audienceBACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage. METHODS: Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects. RESULTS: The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%. CONCLUSIONS: Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets