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      Between a bug and a hard place: Trypanosoma cruzi genetic diversity and the clinical outcomes of Chagas disease

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          Abstract

          Over the last 30 years, concomitant with successful transnational disease control programs across Latin America, Chagas disease has expanded from a neglected, endemic parasitic infection of the rural poor to an urbanized chronic disease, and now a potentially emergent global health problem. Trypanosoma cruzi infection has a highly variable clinical course, ranging from complete absence of symptoms to severe and often fatal cardiovascular and/or gastrointestinal manifestations. To date, few correlates of clinical disease progression have been identified. Elucidating a putative role for T. cruzi strain diversity in Chagas disease pathogenesis is complicated by the scarcity of parasites in clinical specimens and the limitations of our contemporary genotyping techniques. This article systematically reviews the historical literature, given our current understanding of parasite genetic diversity, to evaluate the evidence for any association between T. cruzi genotype and chronic clinical outcome, risk of congenital transmission or reactivation and orally transmitted outbreaks.

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          Most cited references324

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          The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.

          Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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            The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications.

            The protozoan Trypanosoma cruzi, its mammalian reservoirs, and vectors have existed in nature for millions of years. The human infection, named Chagas disease, is a major public health problem for Latin America. T. cruzi is genetically highly diverse and the understanding of the population structure of this parasite is critical because of the links to transmission cycles and disease. At present, T. cruzi is partitioned into six discrete typing units (DTUs), TcI-TcVI. Here we focus on the current status of taxonomy-related areas such as population structure, phylogeographical and eco-epidemiological features, and the correlation of DTU with natural and experimental infection. We also summarize methods for DTU genotyping, available for widespread use in endemic areas. For the immediate future multilocus sequence typing is likely to be the gold standard for population studies. We conclude that greater advances in our knowledge on pathogenic and epidemiological features of these parasites are expected in the coming decade through the comparative analysis of the genomes from isolates of various DTUs. Copyright © 2012 Elsevier B.V. All rights reserved.
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              Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

              Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. 1,2 Here we describe methods for large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short term culture. Analysis of 86,158 exonic SNPs that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.
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                Author and article information

                Journal
                Expert Rev Anti Infect Ther
                Expert Rev Anti Infect Ther
                IERZ
                ierz20
                Expert Review of Anti-Infective Therapy
                Informa Healthcare
                1478-7210
                1744-8336
                3 August 2015
                10 July 2015
                : 13
                : 8
                : 995-1029
                Affiliations
                [ a ] 1Department of Pathogen Molecular Biology, Faculty of Infectious Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
                [ b ] 2Global Health Sciences, Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA, USA
                Author notes
                *Author for correspondence: Caryn.Bern2@ 123456ucsf.edu
                Article
                1056158
                10.1586/14787210.2015.1056158
                4784490
                26162928
                2d30d6bb-c2bf-4e18-9e98-6e9aa0eae9bf
                © 2015 Taylor & Francis

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 0, Tables: 8, Equations: 0, References: 341, Pages: 35
                Categories
                Review
                Review

                cardiomyopathy,• chagas disease,congenital transmission,diagnostics,genetic diversity,oral outbreaks,reactivation,treatment

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