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Concept: Chagas disease

169

Anthropogenic land use may influence transmission of multi-host vector-borne pathogens by changing diversity, relative abundance, and community composition of reservoir hosts. These reservoir hosts may have varying competence for vector-borne pathogens depending on species-specific characteristics, such as life history strategy. The objective of this study is to evaluate how anthropogenic land use change influences blood meal species composition and the effects of changing blood meal species composition on the parasite infection rate of the Chagas disease vector Rhodnius pallescens in Panama.

Concepts: Immune system, Infectious disease, Malaria, Chagas disease, Trypanosoma, Trypanosoma cruzi, Triatominae, Natural reservoir

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BACKGROUND: With declining vectorial transmission, Chagas disease predominantly affects adults nowadays. The efficacy of nifurtimox in the chronic phase in adult patients is poorly known, particularly in regions where there is no risk of reinfection. Recommendations for treatment outcome assessment rely on serological follow-up. We evaluated the serological and parasitological response to nifurtimox in a cohort of adult patients three years post-treatment in Switzerland. METHODS: Patients treated with nifurtimox in 2008 during a cross-sectional study in Geneva, Switzerland, were contacted for follow-up in 2011. Two ELISAs and a rapid immunochromatographic test were used to test 2008 and 2011 serum samples simultaneously. In addition, conventional and real-time PCR were performed on 2011 samples. RESULTS: Thirty-seven (84.1%) of 44 eligible patients, predominantly female, middle-aged, Bolivians at the indeterminate stage, were enrolled. All 2011 ELISA and immunochromatographic tests were positive. Twenty-eight (75.7%) patients presented a lower optical density (OD) in 2011 compared to 2008. This OD difference was significant in both commercial (P < 0.001) and in-house (P = 0.002) ELISAs. Agreement between the two ELISAs was low (Kappa = 0.469). All patients had negative conventional PCR results but one (2.7%) was positive with real-time PCR. CONCLUSION: Our results highlight the inadequacy of serology for assessing response in adults, three years after treatment. In our cohort, 97.3% had results that could either indicate treatment failure or persistant humoral response despite treatment. The lack of accurate early post-treatment tests of cure prevents appropriate patients information and councelling. New follow-up tests are needed to assess treatments efficacy given the large adult population in need of antiparasitic therapy.

Concepts: Antibody, Epidemiology, Infectious disease, Polymerase chain reaction, Chagas disease, Serology, Antiparasitic, Nifurtimox

167

We studied a small rural community of 411 inhabitants localized in the state of Campeche in the Yucatan Peninsula, Mexico. In 44 collected triatomines captured inside the houses, human feeding source was revealed in 23 of 44 (52%) samples, and chicken feeding source was revealed in 16 of 44 (36%) samples. In a set of 29 triatomines, mouse was the feeding source in 13 (44%) samples, and dog was the feeding source in 7 (24%) samples. Infection index with Trypanosoma cruzi in collected triatomines was 38%, and all parasites belonged to discrete type unit I. Inhabitants referred high contact with triatomine’s bite in 60 of 128 (47%) samples, but seroprevalence was 2.3% (3/128). Evidence of electrocardiographic alteration compatible with Chagas disease was observed only in one asymptomatic seropositive subject. In conclusion, Triatoma dimidiata in this region are preferentially infected with T. cruzi I and feed on human beings with relative high frequency, but seroprevalence and Chagas disease in humans is relatively low.

Concepts: Infectious disease, Chagas disease, Trypanosoma, Trypanosoma cruzi, Carlos Chagas, Reduviidae, Triatominae, Triatoma

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Trypanosoma cruzi is dispersed in nature through many transmission mechanisms among a high diversity of vectors and mammalian species, representing particular behaviors and habitats. Thus, each locality has a unique set of conditions underlying the maintenance of this parasite in the wild. The aim of the present study was to evaluate the life-cycle of T. cruzi in free-ranging coatis from the central region of the Brazilian Pantanal using a multi-factorial approach.

Concepts: Chagas disease, Trypanosoma, Trypanosoma cruzi, Coati, Procyonidae, Procyonids, South American Coati, Nasua

101

The extraordinary biological diversity of tropical forests harbors a rich chemical diversity with enormous potential as a source of novel bioactive compounds. Of particular interest are new environments for microbial discovery. Sloths - arboreal mammals commonly found in the lowland forests of Panama - carry a wide variety of micro- and macro-organisms on their coarse outer hair. Here we report for the first time the isolation of diverse and bioactive strains of fungi from sloth hair, and their taxonomic placement. Eighty-four isolates of fungi were obtained in culture from the surface of hair that was collected from living three-toed sloths (Bradypus variegatus, Bradypodidae) in Soberanía National Park, Republic of Panama. Phylogenetic analyses revealed a diverse group of Ascomycota belonging to 28 distinct operational taxonomic units (OTUs), several of which are divergent from previously known taxa. Seventy-four isolates were cultivated in liquid broth and crude extracts were tested for bioactivity in vitro. We found a broad range of activities against strains of the parasites that cause malaria (Plasmodium falciparum) and Chagas disease (Trypanosoma cruzi), and against the human breast cancer cell line MCF-7. Fifty fungal extracts were tested for antibacterial activity in a new antibiotic profile screen called BioMAP; of these, 20 were active against at least one bacterial strain, and one had an unusual pattern of bioactivity against Gram-negative bacteria that suggests a potentially new mode of action. Together our results reveal the importance of exploring novel environments for bioactive fungi, and demonstrate for the first time the taxonomic composition and bioactivity of fungi from sloth hair.

Concepts: Breast cancer, Bacteria, Fungus, Chagas disease, Mammal, Three-toed sloth, Sloth, Pale-throated Sloth

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Drugs for neglected tropical diseases (NTD) are being excessively priced in the United States. Benznidazole, the first-line drug for Chagas disease, may become approved by the Food and Drug Administration (FDA) and manufactured by a private company in the US, thus placing it at risk of similar pricing. Chagas disease is an NTD caused by Trypanosoma cruzi; it is endemic to Latin America, infecting 8 million individuals. Human migration has changed the epidemiology causing nonendemic countries to face increased challenges in diagnosing and managing patients with Chagas disease. Only 2 drugs exist with proven efficacy: benznidazole and nifurtimox. Benznidazole has historically faced supply problems and drug shortages, limiting accessibility. In the US, it is currently only available under an investigational new drug (IND) protocol from the CDC and is provided free of charge to patients. However, 2 companies have stated that they intend to submit a New Drug Application (NDA) for FDA approval. Based on recent history of companies acquiring licensing rights for NTD drugs in the US with limited availability, it is likely that benznidazole will become excessively priced by the manufacturer-paradoxically making it less accessible. However, if the companies can be taken at their word, there may be reason for optimism.

Concepts: Infectious disease, United States, Chagas disease, African trypanosomiasis, Food and Drug Administration, Trypanosoma cruzi, Neglected diseases, New Drug Application

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BACKGROUND: As Chagas disease continues to expand beyond tropical and subtropical zones, a growing need exists to better understand its resulting economic burden to help guide stakeholders such as policy makers, funders, and product developers. We developed a Markov simulation model to estimate the global and regional health and economic burden of Chagas disease from the societal perspective. METHODS: Our Markov model structure had a 1 year cycle length and consisted of five states: acute disease, indeterminate disease, cardiomyopathy with or without congestive heart failure, megaviscera, and death. Major model parameter inputs, including the annual probabilities of transitioning from one state to another, and present case estimates for Chagas disease came from various sources, including WHO and other epidemiological and disease-surveillance-based reports. We calculated annual and lifetime health-care costs and disability-adjusted life-years (DALYs) for individuals, countries, and regions. We used a discount rate of 3% to adjust all costs and DALYs to present-day values. FINDINGS: On average, an infected individual incurs US$474 in health-care costs and 0·51 DALYs annually. Over his or her lifetime, an infected individual accrues an average net present value of $3456 and 3·57 DALYs. Globally, the annual burden is $627·46 million in health-care costs and 806 170 DALYs. The global net present value of currently infected individuals is $24·73 billion in health-care costs and 29 385 250 DALYs. Conversion of this burden into costs results in annual per-person costs of $4660 and lifetime per-person costs of $27 684. Global costs are $7·19 billion per year and $188·80 billion per lifetime. More than 10% of these costs emanate from the USA and Canada, where Chagas disease has not been traditionally endemic. A substantial proportion of the burden emerges from lost productivity from cardiovascular disease-induced early mortality. INTERPRETATION: The economic burden of Chagas disease is similar to or exceeds those of other prominent diseases globally (eg, rotavirus $2·0 billion, cervical cancer $4·7 billion) even in the USA (Lyme disease $2·5 billion), where Chagas disease has not been traditionally endemic, suggesting an economic argument for more attention and efforts towards control of Chagas disease. FUNDING: Bill & Melinda Gates Foundation, the National Institute of General Medical Sciences Models of Infectious Disease Agent Study.

Concepts: Medicine, Epidemiology, Infectious disease, Cardiomyopathy, Heart failure, Infection, Chagas disease, Bill & Melinda Gates Foundation

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Background The role of trypanocidal therapy in patients with established Chagas' cardiomyopathy is unproven. Methods We conducted a prospective, multicenter, randomized study involving 2854 patients with Chagas' cardiomyopathy who received benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome in the time-to-event analysis was the first event of any of the components of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event. Results The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.07; P=0.31). At baseline, a polymerase-chain-reaction (PCR) assay was performed on blood samples obtained from 1896 patients; 60.5% had positive results for Trypanosoma cruzi on PCR. The rates of conversion to negative PCR results (PCR conversion) were 66.2% in the benznidazole group and 33.5% in the placebo group at the end of treatment, 55.4% and 35.3%, respectively, at 2 years, and 46.7% and 33.1%, respectively, at 5 years or more (P<0.001 for all comparisons). The effect of treatment on PCR conversion varied according to geographic region: in Brazil, the odds ratio for PCR conversion was 3.03 (95% CI, 2.12 to 4.34) at 2 years and 1.87 (95% CI, 1.33 to 2.63) at 5 or more years; in Colombia and El Salvador, the odds ratio was 1.33 (95% CI, 0.90 to 1.98) at 2 years and 0.96 (95% CI, 0.63 to 1.45) at 5 or more years; and in Argentina and Bolivia, the odds ratio was 2.63 (95% CI, 1.89 to 3.66) at 2 years and 2.79 (95% CI, 1.99 to 3.92) at 5 or more years (P<0.001 for interaction). However, the rates of PCR conversion did not correspond to effects on clinical outcome (P=0.16 for interaction). Conclusions Trypanocidal therapy with benznidazole in patients with established Chagas' cardiomyopathy significantly reduced serum parasite detection but did not significantly reduce cardiac clinical deterioration through 5 years of follow-up. (Funded by the Population Health Research Institute and others; ClinicalTrials.gov number, NCT00123916 ; Current Controlled Trials number, ISRCTN13967269 .).

Concepts: Clinical trial, Myocardial infarction, Cardiology, Randomized controlled trial, Implantable cardioverter-defibrillator, Chagas disease, Ventricular tachycardia, Ventricular fibrillation

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Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually1. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drug(s) modulating the activity of a conserved parasite target2. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

Concepts: Immune system, Disease, Infectious disease, Bacteria, Chagas disease, Inhibitor, Trypanosoma, Trypanosoma cruzi

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In this study, we evaluated the long-term efficacy of a two-component subunit vaccine against Trypanosoma cruzi infection. C57BL/6 mice were immunized with TcG2/TcG4 vaccine delivered by a DNA-prime/Protein-boost (D/P) approach and challenged with T. cruzi at 120 or 180 days post-vaccination (dpv). We examined whether vaccine-primed T cell immunity was capable of rapid expansion and intercepting the infecting T. cruzi. Our data showed that D/P vaccine elicited CD4+ (30-38%) and CD8+ (22-42%) T cells maintained an effector phenotype up to 180 dpv, and were capable of responding to antigenic stimulus or challenge infection by a rapid expansion (CD8>CD4) with type 1 cytokine (IFNγ+ and TFNα+) production and cytolytic T lymphocyte (CTL) activity. Subsequently, challenge infection at 120 or 180 dpv, resulted in 2-3-fold lower parasite burden in vaccinated mice than was noted in unvaccinated/infected mice. Co-delivery of IL-12- and GMCSF-encoding expression plasmids provided no significant benefits in enhancing the anti-parasite efficacy of the vaccine-induced T cell immunity. Booster immunization (bi) with recombinant TcG2/TcG4 proteins 3-months after primary vaccine enhanced the protective efficacy, evidenced by an enhanced expansion (1.2-2.8-fold increase) of parasite-specific, type 1 CD4+ and CD8+ T cells and a potent CTL response capable of providing significantly improved (3-4.5-fold) control of infecting T. cruzi. Further, CD8+T cells in vaccinated/bi mice were predominantly of central memory phenotype, and capable of responding to challenge infection 4-6-months post bi by a rapid expansion to a poly-functional effector phenotype, and providing a 1.5-2.3-fold reduction in tissue parasite replication. We conclude that the TcG2/TcG4 D/P vaccine provided long-term anti-T. cruzi T cell immunity, and bi would be an effective strategy to maintain or enhance the vaccine-induced protective immunity against T. cruzi infection and Chagas disease.

Concepts: Immune system, Gene, Infectious disease, Bacteria, Vaccination, Chagas disease, B cell, Trypanosoma cruzi