Chagas Disease in the United States: a Public Health Approach

Bern, Caryn; Messenger, Louisa A.; Whitman, Jeffrey D.; Maguire, James H.

doi:10.1128/cmr.00023-19

Cited by 182 publications

(223 citation statements)

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“…Chagas disease is endemic in many areas of Latin America, and is a particular problem amongst the rural poor, where an estimated 6-7 million people are infected with the causative agent, the protozoan parasite Trypanosoma cruzi [1]. The disease has also become a global health problem, with several hundred thousand infected individuals within migrant populations, mainly in the USA and Europe [2,3]. The principal route of T. cruzi infection is via hematophagous triatomine bugs, although oral (contaminated food and drink) and congenital transmission are also important, along with blood transfusion and organ transplantation.…”

Section: Introductionmentioning

confidence: 99%

Challenges in Chagas Disease Drug Development

et al. 2020

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The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge of disease pathogenesis, parasite biology and drug activity. Nevertheless, several factors have come together to create a more optimistic scenario. Drug-based research has become more systematic, with increased collaborations between the academic and commercial sectors, often within the framework of not-for-profit consortia. High-throughput screening of compound libraries is being widely applied, and new technical advances are helping to streamline the drug development pipeline. In addition, drug repurposing and optimisation of current treatment regimens, informed by laboratory research, are providing a basis for new clinical trials. Here, we will provide an overview of the current status of Chagas disease drug development, highlight those areas where progress can be expected, and describe how fundamental research is helping to underpin the process.

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Section: Introductionmentioning

confidence: 99%

Challenges in Chagas Disease Drug Development

et al. 2020

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“…The life cycle of T. cruzi is complex and involves the epimastigote and amastigote replicative stages in the invertebrate and vertebrate hosts respectively, and the trypomastigote infective stage (15). In the hematophagous invertebrate host, parasites must thrive in a pro-oxidant microenvironment caused by the blood degradation and heme release (16).…”

Section: Introductionmentioning

confidence: 99%

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

Costa

et al. 2020

Preprint

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The protozoan Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6-7 million people worldwide. The parasite presents high biological diversity, reflecting on the inefficiency of benznidazole in chronic or older patients. ABC superfamily proteins contain active transporters involved in the xenobiotic and endobiotic efflux and overexpressed in MDR cells. An ABCC-like transport was identified in the T. cruzi Y strain, being able to extrude thiol-conjugated compounds. As non-protein thiols represent prime line of defense towards reactive species, ABCC-like activity could participate in the regulation of mediators implicated in responses to cellular stress arising from a variety of stimuli, as environmental or chemotherapeutic. This study shows that T. cruzi ABCC-like protein transports GSH, GSSG and ceramides, all implicated in cellular stress. Hemin, representative from the hematophagous feeding of the vector, was transported as well, suggesting a role for ABCC as a metal-thiol transporter. In addition, all strains evaluated showed ABCC-like activity, while no ABCB1-like activity was detected. Also, results suggest that ABCC-like does not associate to natural resistance to benznidazole, considering that the sensitive strains CL Brener and Berenice showed higher ABCC-like activity than the resistant strains Y and Colombiana. Instead, ABCC-like efflux increased after continuous exposure of Y strain to benznidazole. Moreover, ABCC does not perform direct efflux of drug and its participation in the machinery of protection against stress depends on the efflux of metabolites in conjugation to or in cotransport with thiol.

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“…Oral, congenital and blood transfusion are other important transmission routes. 6-7 million people in Latin America are infected with T. cruzi (1), and as a result of migration, there are now hundreds of thousands of infected individuals in non-endemic regions, particularly the USA and Europe (2,3).…”

Section: Introductionmentioning

confidence: 99%

In vivo analysis of Trypanosoma cruzi persistence foci at single cell resolution

Ward

Lewis

Khan

et al. 2020

Preprint

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247 23 Text: 4892 24 25 2 ABSTRACT Infections with Trypanosoma cruzi are usually life-long despite 26 generating a strong adaptive immune response. Identifying the sites of parasite 27persistence is therefore crucial to understand how T. cruzi avoids immune-mediated 28 destruction. However, this is a major technical challenge because the parasite burden 29 during chronic infections is extremely low. Here, we describe an integrated approach 30 involving comprehensive tissue processing, ex vivo imaging, and confocal 31 microscopy, which has allowed us to visualise infected host cells in murine tissue, with 32 exquisite sensitivity. Using bioluminescence-guided tissue sampling, with a detection 33 level of <20 parasites, we show that in the colon, smooth muscle myocytes in the 34 circular muscle layer are the most common infected host cell type. Typically, during 35 chronic infections, the entire colon of a mouse contains only a few hundred parasites, 36 often concentrated in a small number of cells containing >200 parasites, that we term 37 mega-nests. In contrast, during the acute stage, when the total parasite burden is 38 considerably higher and many cells are infected, nests containing >50 parasites are 39 rarely found. In C3H/HeN mice, but not BALB/c, we identified skeletal muscle as a 40 major site of persistence during the chronic stage, with most parasites found in large 41 mega-nests within the muscle fibres. Finally, we report that parasites are also 42 frequently found in the skin during chronic murine infections, often in multiple infection 43 foci. In addition to being a site of parasite persistence, this anatomical reservoir could 44 play an important role in insect-mediated transmission, and have implications for drug 45 development. 46 47 48 49 3 IMPORTANCE Trypanosoma cruzi causes Chagas disease, the most important 50 parasitic infection in Latin America. Major pathologies include severe damage to the 51 heart and digestive tract, although symptoms do not usually appear until decades after 52 infection. Research has been hampered by the complex nature of the disease and 53 technical difficulties in locating the extremely low number of parasites. Here, using 54 highly sensitive imaging technology, we reveal the sites of parasite persistence in 55 experimental mice at single-cell resolution. We show that parasites are frequently 56 located in smooth muscle cells in the circular muscle layer of the colon, and that 57 skeletal muscle cells and the skin can also be important reservoirs. This information 58 provides a framework for investigating how the parasite is able to survive as a life-long 59 infection, despite a vigorous immune response. It also informs drug-development 60 strategies by identifying tissue sites that must be accessed to achieve a curative 61 outcome.62 63 64 65 66 KEY WORDS: Trypanosoma cruzi, Chagas disease, chronic persistence, murine 67 imaging, colon, skeletal muscle, skin 68 69 70 71 72 73 74 4 INTRODUCTION The intracellular protozoan parasite Trypanosoma cruzi is the...

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Chagas Disease in the United States: a Public Health Approach

Cited by 182 publications

References 331 publications

Challenges in Chagas Disease Drug Development

Challenges in Chagas Disease Drug Development

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

In vivo analysis of Trypanosoma cruzi persistence foci at single cell resolution

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