Views on the autoimmunity hypothesis for Chagas disease pathogenesis

Initially, the notion that the pathogenesis of Chagas disease has an autoimmune component was based on the finding that sera from Trypanosoma cruzi-infected patients or laboratory animals contain antibodies that recognize both parasite and host tissue antigens. Subsequent work suggested that T lymphocytes from chagasic patients and animals also displayed such cross-reactivity. However, the autoimmunity hypothesis has remained controversial because of experimental pitfalls, incomplete or inadequate controls, difficulties in reproducing some key results, and a lack of persuasive evidence that the cross-reactive antibodies or lymphocytes can truly effect the multifaceted pathological features of Chagas disease. Whether the immunologic autoreactivities described to date cause chagasic pathology or result from it is another unresolved question. Discussed herein are the most recent contributions to this topic and the reservations they have raised.     

Prevention of congenital Chagas through treatment of girls and women of childbearing age

It is currently unknown whether treatment of Chagas disease decreases the risk ofcongenital transmission from previously treated mothers to their infants. In a cohortof women with Chagas disease previously treated with benznidazole, no congenitaltransmission of the disease was observed in their newborns. This finding providessupport for the treatment of Chagas disease as early as possible.     

Behavioural alterations are independent of sickness behaviour in chronic experimental Chagas disease

The existence of the nervous form of Chagas disease is a matter of discussion sinceCarlos Chagas described neurological disorders, learning and behavioural alterationsin Trypanosoma cruzi-infected individuals. In most patients, theclinical manifestations of the acute phase, including neurological abnormalities,resolve spontaneously without apparent consequence in the chronic phase of infection.However, chronic Chagas disease patients have behavioural changes such as psychomotoralterations, attention and memory deficits, and depression. In the present study, wetested whether or not behavioural alterations are reproducible in experimentalmodels. We show that C57BL/6 mice chronically infected with the Colombian strain ofT. cruzi (150 days post-infection) exhibit behavioural changes as(i) depression in the tail suspension and forced swim tests, (ii) anxiety analysed byelevated plus maze and open field test sand and (iii) motor coordination in therotarod test. These alterations are neither associated with neuromuscular disordersassessed by the grip strength test nor with sickness behaviour analysed bytemperature variation sand weight loss. Therefore, chronically T.cruzi-infected mice replicate behavioural alterations (depression andanxiety) detected in Chagas disease patients opening an opportunity to study theinterconnection and the physiopathology of these two biological processes in aninfectious scenario.     

Reaching for the Holy Grail: insights from infection/cure models on the prospects for vaccines for Trypanosoma cruzi infection

Prevention of Trypanosoma cruzi infection in mammals likely depends on either prevention of the invading trypomastigotes from infecting host cells or the rapid recognition and killing of the newly infected cells by T. cruzi-specific T cells. We show here that multiple rounds of infection and cure (by drug therapy) fails to protect mice from reinfection, despite the generation of potent T cell responses. This disappointing result is similar to that obtained with many other vaccine protocols used in attempts to protect animals from T. cruzi infection. We have previously shown that immune recognition of T. cruzi infection is significantly delayed both at the systemic level and at the level of the infected host cell. The systemic delay appears to be the result of a stealth infection process that fails to trigger substantial innate recognition mechanisms while the delay at the cellular level is related to the immunodominance of highly variable gene family proteins, in particular those of the trans-sialidase family. Here we discuss how these previous studies and the new findings herein impact our thoughts on the potential of prophylactic vaccination to serve a productive role in the prevention of T. cruzi infection and Chagas disease.     

Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease

This work describes the antitrypanocidal activity of two hydroxamic acid derivatives containing o-ethoxy (HAD1) and p-ethoxy (HAD2) as substituent in the aromatic ring linked to the isoxazoline ring. HAD1 and HAD2 induced a significant reduction in the number of intracellular parasites and consequently showed activity on the multiplication of the parasite. Treatment of cardiomyocytes and macrophages with the compounds revealed no significant loss in cell viability. Ultrastructural alterations after treatment of cardiomyocytes or macrophages infected by Trypanosoma cruzi with the IC₅₀ value of HAD1 revealed alterations to amastigotes, showing initial damage seen as swelling of the kinetoplast. This gave a good indication of the ability of the drug to permeate through the host cell membrane as well as its selectivity to the parasite target. Both compounds HAD1 and 2 were able to reduce the cysteine peptidases and decrease the activity of metallopeptidases     

Commercial enzyme-linked immunosorbent assay versus polymerase chain reaction for the diagnosis of chronic Chagas disease: a systematic review and meta-analysis

Chronic Chagas disease diagnosis relies on laboratory tests due to its clinicalcharacteristics. The aim of this research was to review commercial enzyme-linkedimmunosorbent assay (ELISA) and polymerase chain reaction (PCR) diagnostic testperformance. Performance of commercial ELISA or PCR for the diagnosis of chronicChagas disease were systematically searched in PubMed, Scopus, Embase, ISI Web, andLILACS through the bibliography from 1980-2014 and by contact with the manufacturers.The risk of bias was assessed with QUADAS-2. Heterogeneity was estimated with theI² statistic. Accuracies provided by the manufacturers usuallyoverestimate the accuracy provided by academia. The risk of bias is high in mosttests and in most QUADAS dimensions. Heterogeneity is high in either sensitivity,specificity, or both. The evidence regarding commercial ELISA and ELISA-recsensitivity and specificity indicates that there is overestimation. The currentrecommendation to use two simultaneous serological tests can be supported by the riskof bias analysis and the amount of heterogeneity but not by the observed accuracies.The usefulness of PCR tests are debatable and health care providers should not orderthem on a routine basis. PCR may be used in selected cases due to its potential todetect seronegative subjects.     

Urban Chagas disease in children and women in primary care centres in Buenos Aires,Argentina

The primary objective of this study was to estimate the prevalence of this disease inwomen of childbearing age and children treated at health centres in underservicedareas of the city of Buenos Aires. Demographic and Chagas disease status data werecollected. Samples for Chagas disease serology were obtained on filter paper and thereactive results were confirmed with conventional samples. A total of 1,786 subjectswere screened and 73 positive screening results were obtained: 17 were from childrenand 56 were from women. The Trypanosoma cruzi infection risk wasgreater in those individuals who had relatives with Chagas disease, who rememberseeing kissing bugs, who were of Bolivian nationality or were born in the Argentineprovince of Santiago del Estero. The overall prevalence of Chagas disease was 4.08%.Due to migration, Chagas disease is currently predominantly urban. The observedprevalence requires health programme activities that are aimed at urban children andtheir mothers. Most children were infected congenitally, which reinforces the needfor Chagas disease screening of all pregnant women and their babies in Argentina. Theactive search for new cases is important because the appropriate treatment inchildren has a high cure rate.     

Biomarkers of therapeutic responses in chronic Chagas disease: state of the art and future perspectives

The definition of a biomarker provided by the World Health Organization is any substance, structure, or process that can be measured in the body, or its products and influence, or predict the incidence or outcome of disease. Currently, the lack of prognosis and progression markers for chronic Chagas disease has posed limitations for testing new drugs to treat this neglected disease. Several molecules and techniques to detect biomarkers in Trypanosoma cruzi-infected patients have been proposed to assess whether specific treatment with benznidazole or nifurtimox is effective. Isolated proteins or protein groups from different T. cruzi stages and parasite-derived glycoproteins and synthetic neoglycoconjugates have been demonstrated to be useful for this purpose, as have nucleic acid amplification techniques. The amplification of T. cruzi DNA using the real-time polymerase chain reaction method is the leading test for assessing responses to treatment in a short period of time. Biochemical biomarkers have been tested early after specific treatment. Cytokines and surface markers represent promising molecules for the characterisation of host cellular responses, but need to be further assessed.     

A model for Chagas disease with controlled spraying

Chagas disease is a vector-borne parasitic disease that infects mammals, including humans, through much of Latin America. This work presents a mathematical model for the dynamics of domestic transmission in the form of four coupled nonlinear differential equations. The four equations model the number of domiciliary vectors, the number of infected domiciliary vectors, the number of infected humans, and the number of infected domestic animals. The main interest of this work lies in its study of the effects of insecticide spraying and of the recovery of vector populations with cessation of spraying. A novel aspect in the model is that yearly spraying, which is currently used to prevent transmission, is taken into account. The model's predictions for a representative village are discussed. In particular, the model predicts that if pesticide use is discontinued, the vector population and the disease can return to their pre-spraying levels in approximately 5–8 years.     

The main sceneries of Chagas disease transmission. The vectors,blood and oral transmissions - A comprehensive review

This review deals with transmission of Trypanosoma cruzi by the most important domestic vectors, blood transfusion and oral intake. Among the vectors, Triatoma infestans, Panstrongylus megistus, Rhodnius prolixus, Triatoma dimidiata, Triatoma brasiliensis, Triatoma pseudomaculata, Triatoma sordida, Triatoma maculata, Panstrongylus geniculatus, Rhodnius ecuadoriensis and Rhodnius pallescens can be highlighted. Transmission of Chagas infection, which has been brought under control in some countries in South and Central America, remains a great challenge, particularly considering that many endemic countries do not have control over blood donors. Even more concerning is the case of non-endemic countries that receive thousands of migrants from endemic areas that carry Chagas disease, such as the United States of America, in North America, Spain, in Europe, Japan, in Asia, and Australia, in Oceania. In the Brazilian Amazon Region, since Shaw et al. (1969) described the first acute cases of the disease caused by oral transmission, hundreds of acute cases of the disease due to oral transmission have been described in that region, which is today considered to be endemic for oral transmission. Several other outbreaks of acute Chagas disease by oral transmission have been described in different states of Brazil and in other South American countries.     

Acute Chagas disease in El Salvador 2000-2012 - Need for surveillance and control

Several parasitological studies carried out in El Salvador between 2000-2012 showed ahigher frequency of acute cases of Chagas disease than that in other Central Americancountries. There is an urgent need for improved Chagas disease surveillance andvector control programs in the provinces where acute Chagas disease occurs andthroughout El Salvador as a whole.     

Atlas of Mexican Triatominae (Reduviidae: Hemiptera) and vector transmission of Chagas disease

Chagas disease is one of the most important yet neglected parasitic diseases in Mexico and is transmitted by Triatominae. Nineteen of the 31 Mexican triatomine species have been consistently found to invade human houses and all have been found to be naturally infected with Trypanosoma cruzi. The present paper aims to produce a state-of-knowledge atlas of Mexican triatomines and analyse their geographic associations with T. cruzi, human demographics and landscape modification. Ecological niche models (ENMs) were constructed for the 19 species with more than 10 records in North America, as well as for T. cruzi. The 2010 Mexican national census and the 2007 National Forestry Inventory were used to analyse overlap patterns with ENMs. Niche breadth was greatest in species from the semiarid Nearctic Region, whereas species richness was associated with topographic heterogeneity in the Neotropical Region, particularly along the Pacific Coast. Three species, Triatoma longipennis, Triatoma mexicana and Triatoma barberi, overlapped with the greatest numbers of human communities, but these communities had the lowest rural/urban population ratios. Triatomine vectors have urbanised in most regions, demonstrating a high tolerance to human-modified habitats and broadened historical ranges, exposing more than 88% of the Mexican population and leaving few areas in Mexico without the potential for T. cruzi transmission.     

Ecoepidemiology,short history and control of Chagas disease in the endemic countries and the new challenge for non-endemic countries

Chagas disease is maintained in nature through the interchange of three cycles: the wild, peridomestic and domestic cycles. The wild cycle, which is enzootic, has existed for millions of years maintained between triatomines and wild mammals. Human infection was only detected in mummies from 4,000-9,000 years ago, before the discovery of the disease by Carlos Chagas in 1909. With the beginning of deforestation in the Americas, two-three centuries ago for the expansion of agriculture and livestock rearing, wild mammals, which had been the food source for triatomines, were removed and new food sources started to appear in peridomestic areas: chicken coops, corrals and pigsties. Some accidental human cases could also have occurred prior to the triatomines in peridomestic areas. Thus, triatomines progressively penetrated households and formed the domestic cycle of Chagas disease. A new epidemiological, economic and social problem has been created through the globalisation of Chagas disease, due to legal and illegal migration of individuals infected by Trypanosoma cruzi or presenting Chagas disease in its varied clinical forms, from endemic countries in Latin America to non-endemic countries in North America, Europe, Asia and Oceania, particularly to the United States of America and Spain. The main objective of the present paper was to present a general view of the interchanges between the wild, peridomestic and domestic cycles of the disease, the development of T. cruzi among triatomine, their domiciliation and control initiatives, the characteristics of the disease in countries in the Americas and the problem of migration to non-endemic countries.     

Cardiomyocyte dysfunction during the chronic phase of Chagas disease

Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of heart failure. We investigated modifications in the cellular electrophysiological and calcium-handling characteristics of an infected mouse heart during the chronic phase of the disease. The patch-clamp technique was used to record action potentials (APs) and L-type Ca²⁺ and transient outward K⁺ currents. [Ca²⁺]_i changes were determined using confocal microscopy. Infected ventricular cells showed prolonged APs, reduced transient outward K⁺ and L-type Ca²⁺ currents and reduced Ca²⁺ release from the sarcoplasmic reticulum. Thus, the chronic phase of Chagas disease is characterised by cardiomyocyte dysfunction, which could lead to heart failure.     

The in vitro activity of fatty diamines and amino alcohols against mixed amastigote and trypomastigote Trypanosoma cruzi forms

Four diamines and three amino alcohols derived from 1-decanol, 1-dodecanol and 1,2-dodecanediol were evaluated in an in vitro assay against a mixture of trypomastigote and intracellular amastigote forms of Trypanosoma cruzi. Two of these compounds (6 and 7) showed better activity against both proliferative stages of T. cruzi than the positive control benznidazole, three were of similar potency (1, 2 and 5) and two were less active (3 and 4).     

In vitro activity of 1,3-bisaryloxypropanamines against Trypanosoma cruzi-infected L929 cultures

We describe herein the antitrypanosomal activity of 20 novel 1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory concentrationvalues in the range of 6-18 µM. In the cytotoxicity tests against L929 cells, only compound 4 presented selectivity index value above 10, indicating low toxicity.     

Congenital transmission of Trypanosoma cruzi in central Brazil. A study of 1,211 individuals born to infected mothers

Transmission of Trypanosoma cruzi during pregnancy is estimated tooccur in less than 20% of infected mothers; however, the etiopathogenesis is notcompletely understood. The Centre for Studies on Chagas Disease provides confirmationof T. cruzi infection for individuals living in central Brazil.In this retrospective hospital-based study, all requests for diagnosis of T.cruzi infection in individuals less than 21 years old from 1994-2014 weresearched. We end with 1,211 individuals and their respective infected mothers.Congenital transmission of infection was confirmed in 24 individuals (2%) in centralBrazil, an area where the main T. cruzi lineage circulating inhumans is TcII. This low prevalence of congenital Chagas disease is discussed inrelation to recent findings in the south region of Brazil, where TcV is the mainlineage and congenital transmission has a higher prevalence (approximately 5%),similar to frequencies reported in Argentina, Paraguay and Bolivia. This is the firstreport to show geographical differences in the rates of congenital transmissionof T. cruzi and the relationship between the prevalence ofcongenital transmission and the type of Tc prevalent in each region.     

Positive deviance study to inform a Chagas disease control program in southern Ecuador

Chagas disease is caused by Trypanosoma cruzi, which is mainly transmitted by the faeces of triatomine insects that find favourable environments in poorly constructed houses. Previous studies have documented persistent triatomine infestation in houses in the province of Loja in southern Ecuador despite repeated insecticide and educational interventions. We aim to develop a sustainable strategy for the interruption of Chagas disease transmission by promoting living environments that are designed to prevent colonisation of rural houses by triatomines. This study used positive deviance to inform the design of an anti-triatomine prototype house by identifying knowledge, attitudes and practices used by families that have remained triatomine-free (2010-2012). Positive deviants reported practices that included maintenance of structural elements of the house, fumigation of dwellings and animal shelters, sweeping with "insect repellent" plants and relocation of domestic animals away from the house, among others. Participants favoured construction materials that do not drastically differ from those currently used (adobe walls and tile roofs). They also expressed their belief in a clear connection between a clean house and health. The family''s economic dynamics affect space use and must be considered in the prototype''s design. Overall, the results indicate a positive climate for the introduction of housing improvements as a protective measure against Chagas disease in this region.     

Determinants of the domiciliary density of Triatoma infestans, vector of Chagas disease

In two heavily infested rural villages of Santiago del Estero, Argentina, where no indoor-spraying with residual insecticides had ever been carried out by official control services, we studied the influence of roof and wall structure, domestic use of insecticide, family size and the number of domestic dogs, on the domiciliary density of Triatoma infestans (Klug). Bug density was significantly associated with (1) the interaction between insecticide use and type of roof, (2) the structure of indoor walls, (3) the number of dogs sharing sleeping areas of people (room-mate dogs), and (4) the number of people plus room-mate dogs, but not with just the number of people resident in the house. The interaction between insecticide use and a roof made of 'simbol', a locally available grass (Pennisetum sp.), also reflected a younger age structure of domestic bug populations. In infested houses, the density of bugs infected with Trypanosoma cruzi Chagas was significantly correlated with overall bug density. Our data suggest that the application of environmental management measures by the affected people, such as plastering of walls and modification of roofs, coupled with keeping dogs away from bedrooms and application of insecticides, should limit the domestic population density of T. infestans and thus reduce the transmission of T. cruzi to people.     

Triatominae species of Suriname (Heteroptera: Reduviidae) and their role as vectors of Chagas disease

Nine species of Triatominae, representing three tribes and five genera, are currentlyknown in Suriname. An annotated list of the species based on the collections of theBureau of Public Health (Suriname), the National Zoological Collection Suriname andthe National History Museum Leiden (the Netherlands) is provided. Additionally, theresults of several years of opportunistic collection in two domestic environments arepresented. The most common species are Rhodnius pictipes Stål,1972, Rhodnius robustus Larrouse, 1972 and Panstrongylusgeniculatus (Latreille, 1811). The significance of the species as vectorsof Chagas disease in Suriname is discussed.