Cutting Edge: Augmenting Muscle MHC Expression Enhances Systemic Pathogen Control at the Expense of T Cell Exhaustion.

Myocytes express low levels of MHC class I (MHC I), perhaps influencing the ability of CD8+ T cells to efficiently detect and destroy pathogens that invade muscle. Trypanosoma cruzi infects many cell types but preferentially persists in muscle, and we asked if this tissue-dependent persistence was linked to MHC expression. Inducible enhancement of skeletal muscle MHC I in mice during the first 20 d of T. cruzi infection resulted in enhanced CD8-dependent reduction of parasite load. However, continued overexpression of MHC I beyond 30 d ultimately led to a collapse of systemic parasite control associated with immune exhaustion, which was reversible in part by blocking PD-1:PD-L1 interactions. These studies demonstrate a surprisingly strong and systemically dominant effect of skeletal muscle MHC expression on maintaining T cell function and pathogen control and argue that the normally low MHC I expression in skeletal muscle is host protective by allowing for pathogen control while preventing immune exhaustion.

Burden of Chagas disease in Brazil, 1990-2016: findings from the Global Burden of Disease Study 2016.

Chagas disease continues to be an important cause of morbidity, mortality and disability in several Latin American countries, including Brazil. Using findings from the Global Burden of Disease Study 2016 (GBD, 2016), we present years of life lost, years lived with disability, and disability-adjusted life years due to Chagas disease in Brazil, by sex, age group, and Brazilian states, from 1990 to 2016. Results are reported in absolute numbers and age-standardized rates (per 100,000 population) with 95% uncertainty intervals. In 2016, 141,640 disability-adjusted life years (95% uncertainty intervals: 129,065-155,941) due to Chagas disease were estimated in Brazil, with a relative reduction of 36.7% compared with 1990 (223,879 disability-adjusted life years (95% uncertainty intervals: 209,372-238,591)). Age-standardized disability-adjusted life year rates declined at the national level (-69.7%) and in all Brazilian states between 1990 and 2016, but with different regional patterns. The decrease in the disability-adjusted life year rates was driven primarily by a consistent reduction in the years of life lost rates, the main component of total disability-adjusted life years for Chagas disease. The highest fatal and non-fatal burden due to Chagas disease was observed among males, the elderly, and in those Brazilian states encompassing important endemic areas for vector transmission in the past. Despite the consistent reduction in its burden during the period, Chagas disease is still an important and neglected cause of health lost due to premature mortality and disability in Brazil. Efforts should be made to maintain the political interest and sustainability of surveillance and control actions for Chagas disease, prevent the risk of re-emergence of vector transmission in endemic areas, and provide health care to chronically infected individuals, including early diagnosis and treatment interventions.

Quantitative and histological assessment of maternal-fetal transmission of Trypanosoma cruzi in guinea pigs: An experimental model of congenital Chagas disease.

OBJECTIVE: We evaluated the effect of Trypanosoma cruzi infection on fertility, gestation outcome, and maternal-fetal transmission in guinea pigs (Cavia porcellus). METHODS: Animals were infected with T. cruzi H4 strain (TcI lineage) before gestation (IBG) or during gestation (IDG). Tissue and sera samples of dams and fetuses were obtained near parturition. RESULTS: All IBG and IDG dams were seropositive by two tests, and exhibited blood parasite load of 1.62±2.2 and 50.1±62 parasites/µl, respectively, by quantitative PCR. Histological evaluation showed muscle fiber degeneration and cellular necrosis in all infected dams. Parasite nests were not detected in infected dams by histology. However, qPCR analysis detected parasites-eq/g heart tissue of 153±104.7 and 169.3±129.4 in IBG and IDG dams, respectively. All fetuses of infected dams were positive for anti-parasite IgG antibodies and tissue parasites by qPCR, but presented a low level of tissue inflammatory infiltrate. Fetuses of IDG (vs. IBG) dams exhibited higher degree of muscle fiber degeneration and cellular necrosis in the heart and skeletal tissues. The placental tissue exhibited no inflammatory lesions and amastigote nests, yet parasites-eq/g of 381.2±34.3 and 79.2±84.9 were detected in IDG and IBG placentas, respectively. Fetal development was compromised, and evidenced by a decline in weight, crow-rump length, and abdominal width in both groups. CONCLUSIONS: T. cruzi TcI has a high capacity of congenital transmission even when it was inoculated at a very low dose before or during gestation. Tissue lesions, parasite load, and fetal under development provide evidence for high virulence of the parasite during pregnancy. Despite finding of high parasite burden by qPCR, placentas were protected from cellular damage. Our studies offer an experimental model to study the efficacy of vaccines and drugs against congenital transmission of T. cruzi. These results also call for T. cruzi screening in pregnant women and adequate follow up of the newborns in endemic areas.

Assessment of Galectin-3 Polymorphism in Subjects with Chronic Chagas Disease / Avaliação do Polimorfismo da Galectina-3 em Indivíduos com Doença de Chagas Crônica

AbstractBackground:Galectin-3, a β-galactoside binding lectin, has been described as a mediator of cardiac fibrosis in experimental studies and as a risk factor associated with cardiovascular events in subjects with heart failure. Previous studies have evaluated the genetic susceptibility to Chagas disease in humans, including the polymorphisms of cytokine genes, demonstrating correlations between the genetic polymorphism and cardiomyopathy development in the chronic phase. However, the relationship between the galectin-3 single nucleotide polymorphism (SNP) and phenotypic variations in Chagas disease has not been evaluated.Objective:The present study aimed to determine whether genetic polymorphisms of galectin-3 may predispose to the development of cardiac forms of Chagas disease.Methods:Fifty-five subjects with Chagas disease were enrolled in this observational study. Real-time polymerase chain reaction (PCR) was used for genotyping the variants rs4644 and rs4652 of the galectin-3 gene.Results:For the SNP rs4644, the relative risk for the cardiac form was not associated with the genotypes AA (OR = 0.79, p = 0.759), AC (OR = 4.38, p = 0.058), or CC (OR = 0.39, p = 0.127). Similarly, for the SNP rs4652, no association was found between the genotypes AA (OR = 0.64, p = 0.571), AC (OR = 2.85, p = 0.105), or CC (OR = 0.49, p = 0.227) and the cardiac form of the disease.Conclusion:Our results showed no association between the different genotypes for both SNPs of the galectin-3 gene and the cardiac form of Chagas disease. (Arq Bras Cardiol. 2015; [online].ahead print, PP.0-0).

ResumoFundamento:A galectina-3, uma lectina de ligação à β-galactosidase, foi descrita como um mediador de fibrose cardíaca em estudos experimentais e um fator de risco associado com eventos cardiovasculares em indivíduos com insuficiência cardíaca. Estudos prévios avaliaram a susceptibilidade genética para doença de Chagas em humanos, incluindo polimorfismos dos genes de citocinas, demonstrando correlações entre o polimorfismo genético e o desenvolvimento de cardiomiopatia na fase crônica. No entanto, a relação entre polimorfismos de nucleotídeo único (single nucleotide polymorphism, SNP) e variações fenotípicas na doença de Chagas ainda não foi avaliada.Objetivo:O presente estudo teve como objetivo determinar se os polimorfismos genéticos da galectina-3 podem predispor ao desenvolvimento de formas cardíacas da doença de Chagas.Métodos:Cinquenta e cinco indivíduos com doença de Chagas foram incluídos neste estudo observacional. A genotipagem das variantes rs4644 e rs4652 do gene da galectina-3 foi realizada por PCR (reação em cadeia de polimerase).Resultados:Para o SNP rs4644, não houve associação entre o risco relativo para a forma cardíaca e os genótipos AA (OR = 0,79, p = 0,759), AC (OR = 4,38, p = 0,058), ou CC (OR = 0,39, p = 0,127). Similarmente, para o SNP rs4652, não foi encontrada associação entre os genótipos AA (OR = 0,64, p = 0,571), AC (OR = 2,85, p = 0,105), ou CC (OR = 0,49, p = 0,227) e a forma cardíaca da doença.Conclusão:Nossos resultados não mostraram associação entre os diferentes genótipos para ambos SNPs do gene da galectina-3 e a forma cardíaca da doença de Chagas. (Arq Bras Cardiol. 2015; [online].ahead print, PP.0-0).

Assessment of Galectin-3 Polymorphism in Subjects with Chronic Chagas Disease.

BACKGROUND: Galectin-3, a ß-galactoside binding lectin, has been described as a mediator of cardiac fibrosis in experimental studies and as a risk factor associated with cardiovascular events in subjects with heart failure. Previous studies have evaluated the genetic susceptibility to Chagas disease in humans, including the polymorphisms of cytokine genes, demonstrating correlations between the genetic polymorphism and cardiomyopathy development in the chronic phase. However, the relationship between the galectin-3 single nucleotide polymorphism (SNP) and phenotypic variations in Chagas disease has not been evaluated. OBJECTIVE: The present study aimed to determine whether genetic polymorphisms of galectin-3 may predispose to the development of cardiac forms of Chagas disease. METHODS: Fifty-five subjects with Chagas disease were enrolled in this observational study. Real-time polymerase chain reaction (PCR) was used for genotyping the variants rs4644 and rs4652 of the galectin-3 gene. RESULTS: For the SNP rs4644, the relative risk for the cardiac form was not associated with the genotypes AA (OR = 0.79, p = 0.759), AC (OR = 4.38, p = 0.058), or CC (OR = 0.39, p = 0.127). Similarly, for the SNP rs4652, no association was found between the genotypes AA (OR = 0.64, p = 0.571), AC (OR = 2.85, p = 0.105), or CC (OR = 0.49, p = 0.227) and the cardiac form of the disease. CONCLUSION: Our results showed no association between the different genotypes for both SNPs of the galectin-3 gene and the cardiac form of Chagas disease.

Assessment of the anti-protozoal activity of crude Carica papaya seed extract against Trypanosoma cruzi.

In order to determine the in vivo activity against the protozoan Trypanosoma cruzi, two doses (50 and 75 mg/kg) of a chloroform extract of Carica papaya seeds were evaluated compared with a control group of allopurinol. The activity of a mixture of the three main compounds (oleic, palmitic and stearic acids in a proportion of 45.9% of oleic acid, 24.1% of palmitic and 8.52% of stearic acid previously identified in the crude extract of C. papaya was evaluated at doses of 100, 200 and 300 mg/kg. Both doses of the extracts were orally administered for 28 days. A significant reduction (p < 0.05) in the number of blood trypomastigotes was observed in animals treated with the evaluated doses of the C. papaya extract in comparison with the positive control group (allopurinol 8.5 mg/kg). Parasitemia in animals treated with the fatty acids mixture was also significantly reduced (p < 0.05), compared to negative control animals. These results demonstrate that the fatty acids identified in the seed extracts of C. papaya (from ripe fruit) are able to reduce the number of parasites from both parasite stages, blood trypomastigote and amastigote (intracellular stage).

[The pampiniform plexus in the chronic phase of human Chagas disease: histologic assessment]. / O plexo pampiniforme na fase crônica da doença de Chagas humana: avaliação histológica.

The occurrence of Trypanosoma cruzi intracellular clusters and phlebitis was searched for on pampiniform plexus vein walls of chronic chagasic patients. For this purpose, 23 pairs of spermatic cords, epididymides and testes (17 from chagasic patients and 6 from non-chagasic controls) were obtained, at autopsy. Trypanosoma cruzi was investigated by immuno-histochemistry on slides obtained from several sections of the gonads and vessels of each case. Only discrete and focal undetermined chronic phlebitis was observed, with no parasites, in 5 chagasics (bilateral in 3) and 2 controls (chi 2: p < 0.10), and discrete mononuclear interstitial infiltration in the funiculi of 13 chagasics and 5 controls (chi 2: p < 0.75). In conclusion, on the contrary to that published regarding the supra-renal central veins, it seems that the hormonal environment provided by testosterone does not favor the infection of the gonadal vessel wall.

Infecçäo experimental de macacos Cebus apella sp pelo Trypanosoma cruzi: avaliaçäo clínica, eletrocardiográfica e anatomopatológica / The experimental infection of Cebus apella sp by Trypanosoma cruzi: its clinical electrocardiography and anatomopathological assessment

Dos trinta e dois macacos capturados no interior do Estado de Säo Paulo e mantidos em laboratório em gaiolas individuais (24 a 25 Cº e 70 por cento de umidificaçäo) após vários xenodiagnósticos negativos, 12 foram infectados por via intraperitoneal com diferentes cepas de Trypanosoma cruzi, cujas formas tripomastigotas injetadas variaram de 1.10**5 a 5.10**6. Os 20 macacos restantes foram mantidos como controle. No período de 1 a 6 anos tanto animais inoculados como os näo inoculados, foram submetidos a xenodiagnóstico e teste sorológico de aglutinaçäo direta, exame clínico e o eletrocardiograma. Posteriormente os macacos foram necropsiados e todos os órgäos submetidos a exame macro e microscópico. O exame clínicos e o eletrocardiograma näo revelaram alteraçöes. Dos 12 macaços infectados, 4 apresentaram evidências de infecçäo ao exame histopatológico: um com formas amastigotas nos tecidos e 3 com miocardite crônica de grau leve. A parasitemia foi comprovada em 66,66 por cento dos animais na fase aguda e a sorologia em 91,66 por cento na fase crônica. Conclui-se que os macacos Cebus näo expressaram suscepitibilidade ao desenvolvimento das lesöes que caracterizam a fase crônica da doença de Chagas mas poderiam ser usados para manter as cepas de T. cruzi e estudos de pesquisa sorológico a longo termo

[The experimental infection of Cebus apella sp. monkeys with Trypanosoma cruzi. Its clinical, electrocardiographic and anatomicopathological assessment]. / Infecção experimental de macacos Cebus apella sp. pelo Trypanosoma cruzi. Avaliaçao clínica, eletrocardiográfica e anatomopatológica.

Thirty-two monkeys were captured and adapted to laboratory conditions captives isolated. They were submitted to multiple xenodiagnosis which were negative. Twelve were infected intraperitoneally with different strains of T. cruzi (1.10(5) to 5.10(6)). Twenty were the control group. Between on to six years both the control group and the infected monkeys, were submitted to xenodiagnosis, serological testing clinical examination and electrocardiography. The clinical examination and the electrocardiogram were always normal. The monkey were autopsied and histological examination detected in the infected group four monkeys with evidence of disease: one with parasites in the tissue and three with chronic myocarditis. Parasitaemia was in 66.66% of the monkeys in the acute phase and the serology was positive in 91.66% in the chronic phase. The authors concluded that Cebus monkeys were not susceptible to the development of the disease but they could be utilized to maintain of such strains and studies of serological research in long-terms infections.

La casa enferma: sociología de la enfermedad de chagas / The sick house: sociology of the chagas disease

La sociología de las enfermedades metaxénicas se encarga de comprender la dimensión individual y social del encuentro vector-parásito-hombre, y los modos como evitarlo, alterando el comportamiento de las personas, la organización social y el medio ambiente construido. Presenta un nuevo enfoque de la sociología como disciplina participante en la prevención del mal de chagas. Como a partir del estudio de una sociedad se puede conocer aún más los entes activos de la misma y como combatirla para poder llegar a una mejor sociedad y así darle a la sociedad un carácter mas científico

Enfermedad de chagas en la Caja Nacional de Salud Policlínico n§ 3: consulta externa / Chagas disease at the patients of the Clinic 3 of the Social Security Health System

Se revisarón 779 carpetas familiares del consultorio de medicina familiar n§ 10 del policonsultorio n§ 32 de la C.N.S. de la ciudad de Cochabamba entre los años 1980 a 1990, constituyendosé un total de 1.892 historias clínicas, obteniendosé 62 casos de pacientes sospechosos (3.28 por ciento) en el aspecto clínico y epidemiológico, identidicándose 35 pacientes (1,84 por ciento) que cumplen los criterios de diagnóstico, corroborados todos ellos por lo menos con dos puebas serológicas positivas. En cuanto a la forma de detección, un 576,13 se presume por la aparición de síntomas, al exámen clínico, pacientes asintomáticos, la presencia de bradicardia es importante, el grupo etáreo entre 34 a 40 años es el mas afectado, en relación al sexo es mas frecuente en el sexo femenino, las formas de presentación mas frecuentes la constituyen la forma Latente y la Crónica, los datos clínicos mas frecuentes hallados fueron las precorfalgias las pálpitaciones y la disnea, presentaron sintomatología gastrointestinal, seis pacientes fueron la bradicardia sinual, bloqueo incompleto, en cuanto a las transtornos radiológicos un 14,29 por ciento presentaron algún grado de cardiomegalia.