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      Trypanosoma cruzi lineage-specific serology: new rapid tests for resolving clinical and ecological associations

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          Abstract

          The protozoan parasite Trypanosoma cruzi, the agent of Chagas disease (American trypanosomiasis), remains a major public health concern in Latin America. The insect vectors are haematophagous triatomine bugs that, during or after their blood meal, pass the infective form of T. cruzi with feces; the parasite can then enter the host through mucosal membranes, the conjunctiva or abraded skin. Other routes of infection are congenital, oral or via blood/organ donation. The acute phase of infection lasts up to a few weeks, with nonspecific, self-resolving symptoms, although deaths can occur in this phase, particularly in children or young adults. The subsequent chronic phase of infection is life-long unless successfully treated, and asymptomatic (indeterminate) in the majority of patients. However, approximately 30% of infected individuals will develop chronic cardiac and/or gastrointestinal pathologies, with sudden death due to chagasic cardiomyopathy [1]. Chronic symptoms may manifest years or decades after the initial infection; currently, there is no prognostic indicator. A recent WHO report estimates that 5–6 million people are infected with T. cruzi [2]. Although vector-borne transmission is confined to the Americas, Chagas disease among migrants from Latin America has become of global health relevance. Trypanosoma cruzi displays remarkable intraspecies diversity, with six genetic lineages (TcI-TcVI) [3], and a proposed seventh, TcBat [4]. The possible association of different lineages of T. cruzi with distinct forms of the disease is a long-standing research interest [5]: the cardiac syndrome is found throughout the endemic area, whereas mega syndromes of the colon and esophagus have rarely been reported beyond the southern cone countries of South America. Trypanosoma cruzi is a zoonosis, with all mammals being susceptible to infection, and humans becoming a later host following the historic peopling of the Americas. The association between T. cruzi lineages, vectors and domestic, peridomestic and sylvatic animals and ecological cycles is complex [6,7]. Investigating the association between infecting lineage(s) and clinical outcome or ecological cycles has faced significant confounding challenges: the sequestration of the parasite in host tissues during the chronic phase, possibly in a lineage-dependent manner, hampers lineage identification by direct genotyping; in vitro culture of isolates may favor the selection of certain lineages. Current serological techniques identify T. cruzi specific antibodies (usually IgG), but are not designed to identify infecting lineage. The possibility therefore arose that serology based on lineage-specific T. cruzi antigens could overcome these difficulties, as it would allow the identification of an individual's history of lineage infection without the need to genotype or isolate the parasite. In 2002, Di Noia and colleagues [8] published a pioneering report on TSSA, a mucin expressed on the mammalian bloodstream form of T. cruzi. This allowed researchers to enter a new era of lineage-specific serology for this parasite. Following the initial characterization, greater diversity of the protein core of TSSA was revealed [9]. There is a short region of the protein core of T. cruzi TSSA where amino acid residues vary according to lineage. Thus, TcI, TcIII and TcIV each have their own potential lineage-specific TSSA epitope; TcII, TcV and TcVI share a common epitope, and the hybrid lineages TcV and TcVI share an additional epitope. Initially, recombinant TSSA proteins encompassing the TcI or TcII/V/VI common epitopes were produced in E. coli, for use in ELISA and western blot. Those reports used sera from mainly southern cone countries, principally Argentina, including those from chronic symptomatic infections [10], pregnant chagasic women [11] and pediatric diagnosis [12]. An alternative approach is to use synthetic peptides (TSSApep-I, -II/V/VI, -III, -IV and -V/VI) representing the lineage-specific epitopes in serological assays. When these were first used in ELISA with sera from a range of South American countries, several novel and unexpected results were found [13]: an association between serological recognition of TSSApep-II/V/VI and degree of clinical symptoms; reaction to TSSApep-II/V/VI was observed in samples from Ecuador and these lineages have rarely been reported in northern South America; specific TSSApep-IV reactions were found in Venezuela and Colombia. Antibody recognition of the current TSSA-I-specific epitope is rare. This may be due to lack of antigenicity or partially because most assayed sera have originated from regions where TcII, TcV and TcVI are predominant (based on genotyping). This observation stimulated research into the function of the native TSSA isoforms, and assessment of their antigenic properties. Canepa and collegues [14] demonstrated that although the TSSA-II/V/VI isoform had a cell binding and entry capacity, causing the authors to ascribe an ‘adhesin’ function, these properties were lacking in the TSSA-I isoform; a subsequent report also proposed that TSSA-II/V/VI had an additional role in T. cruzi differentiation [15]. In terms of antigenicity, both bioinformatic [13] and peptide mapping [16] studies have reinforced the strong antigenicity of the TSSA-II/V/VI common epitope. The proven efficacy of TSSApep-II/V/VI in ELISA stimulated the development of a lateral flow, immunochromatographic rapid diagnostic test (RDT) called Chagas Sero K-SeT, in which this peptide was immobilized on a nitrocellulose membrane, and specific IgG could be detected by protein G conjugate, within 15 min [17]. This novel T. cruzi lineage-specific RDT revealed that in Bolivian patient groups stratified by severity of chagasic cardiomyopathy, RDT seropositivity was five-times higher among patients with severe cardiomyopathy compared with those with no evidence of cardiomyopathy. This was proposed to be due to repeated parasite exposure over time increasing inflammatory cardiac damage in conjunction with an increase in anti-TSSApep-II/V/VI IgG. The same study using Chagas Sero K-SeT also identified sporadic TcII/V/VI infections from Peru. Trypanosoma cruzi has an extremely broad and diverse pattern of circulation among mammals throughout the Americas. Investigation of these natural cycles of infection has led to greatly increased understanding of their natural ecologies, and the transmission risk to human populations. However, the limitations of T. cruzi lineage identification described above apply equally to animals and humans. Thus, lineage-specific serology has also been applied to mammals, initially identifying reactions to the TSSA-II/V/VI isoform in Argentine dogs [18]. Serology using the TSSA synthetic peptides has been extended to sylvatic Brazilian primates, identifying Leontopithecus chrysomelas (golden-headed lion tamarin) and L. rosalia (golden lion tamarin) as natural hosts of TcII and/or TcV/VI in the Atlantic forest of Brazil [19]. The use of Chagas Sero K-SeT with sympatric humans and dogs from northern Argentina has shown the efficacy of protein G for detection across several mammalian orders [20], including primates and rodents (McClean et al. Unpublished Observations), thus reducing the need for species-specific secondary antibodies. The use of Protein G and/or Protein A for IgG detection may further extend this range. However, as with human sera, a test for TSSA-I remains elusive. The lack of reactivity to TSSA-I has led to further efforts to identify an alternative robust TcI antigen. Further studies on the TcIII and TcIV epitopes are clearly warranted. This program of research on T. cruzi demonstrates the value and impact of lineage-specific serology. The point-of-care/capture format of the test provides a result in 15 min and is applicable to animals or patients in rural field locations, without access to a laboratory. This enables low cost rapid surveillance for T. cruzi lineages among potential animal reservoirs of infection, to assess the risk of emergent endemic regions and to guide control strategies, without the need to isolate T. cruzi from the animals. Furthermore, we can far more efficiently investigate whether the genetically distinct T. cruzi lineages may be responsible for the different clinical presentations and prognoses of Chagas disease. This approach also clearly has potential wider application to other infectious diseases.

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          Most cited references 19

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          Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association

          Chagas disease, resulting from the protozoan Trypanosoma cruzi, is an important cause of heart failure, stroke, arrhythmia, and sudden death. Traditionally regarded as a tropical disease found only in Central America and South America, Chagas disease now affects at least 300 000 residents of the United States and is growing in prevalence in other traditionally nonendemic areas. Healthcare providers and health systems outside of Latin America need to be equipped to recognize, diagnose, and treat Chagas disease and to prevent further disease transmission.
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            Between a bug and a hard place: Trypanosoma cruzi genetic diversity and the clinical outcomes of Chagas disease

            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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              Molecular identification of Trypanosoma cruzi discrete typing units in end-stage chronic Chagas heart disease and reactivation after heart transplantation.

              One hundred years after the discovery of Chagas disease, it remains a major neglected tropical disease. Chronic Chagas heart disease (cChHD) is the most severe manifestation. Heart transplantation is the proper treatment for end-stage heart failure, although reactivation of disease may result after receipt of immunosuppressive therapy. T. cruzi strains cluster into 6 discrete typing units (DTUs; I-VI) associated with different geographical distribution, transmission cycles and varying disease symptoms. In the southern cone of South America, T. cruzi II, V, and VI populations appear to be associated with Chagas disease and T. cruzi I with sylvatic cycles. Molecular characterization of DTUs, T. cruzi I genotypes (on the basis of spliced-leader gene polymorphisms), and minicircle signatures was conducted using cardiac explant specimens and blood samples obtained from a cohort of 16 Argentinean patients with cChHD who underwent heart transplantation and from lesion samples obtained from 6 of these patients who presented with clinical reactivation of Chagas disease. Parasite persistence was associated with myocarditis progression, revealing T. cruzi I (genotype Id) in 3 explant samples and T. cruzi II, V, or VI in 5 explant samples. Post-heart transplantation follow-up examination of bloodstream DTUs identified T. cruzi I in 5 patients (genotypes Ia or Id) and T. cruzi II, V, or VI in 7 patients. T. cruzi I, V, and VI were detected in skin chagoma specimens, and T. cruzi V and VI were detected in samples obtained from patients with myocarditis reactivations. Multiple DTUs or genotypes at diverse body sites and polymorphic minicircle signatures at different cardiac regions revealed parasite histotropism. T. cruzi I infections clustered in northern Argentina (latitude, 23 degrees S-27 degrees S), whereas T. cruzi II, V, or VI DTUs were more ubiquitous. Multiple DTUs coexist in patients with Chagas disease. The frequent finding of T. cruzi I associated with cardiac damage was astounding, revealing its pathogenic role in cChHD at the southern cone.
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                Author and article information

                Journal
                Future Sci OA
                Future Sci OA
                FSOA
                Future Science OA
                Future Science Ltd (London, UK )
                2056-5623
                30 October 2019
                December 2019
                30 October 2019
                : 5
                : 10
                Affiliations
                [1 ]Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK
                Author notes
                [* ]Author for correspondence: tapan.bhattacharyya@ 123456lshtm.ac.uk
                Article
                10.2144/fsoa-2019-0103
                6900971
                © 2019 Tapan Bhattacharyya

                This work is licensed under the Creative Commons Attribution 4.0 License

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                Pages: 3
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