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1
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Harrison RE, Vogel KJ, Etheridge RD. Stable colonization of the kissing bug Rhodnius prolixus by Trypanosoma cruzi Y strain. PLoS Negl Trop Dis 2025; 19:e0012906. [PMID: 40073048 PMCID: PMC11928063 DOI: 10.1371/journal.pntd.0012906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 03/21/2025] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
Trypanosoma cruzi is a single-celled eukaryotic parasite responsible for Chagas disease, a major cause of morbidity and mortality in Central and South America. While the host-pathogen interactions of T. cruzi have been extensively studied in vertebrate models, investigations into its interactions within its insect host remain limited. To address this gap and establish a genetically tractable system for studying parasite-vector dynamics, we conducted quantitative kinetic infection studies using the Y strain of T. cruzi and the model vector Rhodnius prolixus. We began by comparing parasite infection kinetics from two genetically diverse strains of T. cruzi, Brazil and Y, and demonstrated that ingested parasites from both strains transiently expand in the anterior regions of the insect digestive tract with stable colonization occurring in the hindgut over the long term. Notably, we demonstrated that the clonal Y strain, contrary to previous reports, can effectively infect and persist across multiple developmental stages of R. prolixus. Additionally, comparison of movement of parasites versus inert fluorescent microspheres introduced into artificial blood meals suggests that T. cruzi colonization of the R. prolixus gut occurs passively through peristaltic movement during digestion, rather than through active parasite-mediated chemotaxis. These findings highlight the T. cruzi Y strain - R. prolixus model system as a promising tool for the in-depth molecular characterization of parasite-vector interactions, potentially offering new insights into the biology of this neglected and deadly human pathogen.
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Affiliation(s)
- Ruby E Harrison
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America
- Department of Cellular Biology, University of Georgia, Athens, Georgia, United States of America
| | - Kevin J Vogel
- Department of Entomology, University of Georgia, Athens, Georgia, United States of America
| | - Ronald Drew Etheridge
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, United States of America
- Department of Cellular Biology, University of Georgia, Athens, Georgia, United States of America
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2
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Díaz JJAR, Garay AFG, Kayano AM, Holanda R, Francisco AF, Kuehn CC, Soares AM, Vega C, Calderon LDA. Cystatin from Austrelaps superbus snake venom as a model for identifying potential inhibitors of Trypanosoma cruzi cruzain. J Venom Anim Toxins Incl Trop Dis 2025; 31:e20240055. [PMID: 39963262 PMCID: PMC11832194 DOI: 10.1590/1678-9199-jvatitd-2024-0055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 12/19/2024] [Indexed: 02/20/2025] Open
Abstract
Background Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately seven million individuals worldwide, with the highest number of cases in Latin America. CD has two phases, of which the chronic phase is characterized by reduced efficacy in drug therapies. This and other factors make developing new strategies that aim to identify molecules capable of becoming alternatives to or complement current chemotherapy vitally important. Methods Cruzain and AsCystatin were obtained recombinantly through expression in E. coli. Bioinformatic assays were conducted with both molecules, followed by in vitro enzyme inhibition assays. Subsequently, in silico studies allowed for the design of peptides, which were then assessed for molecular interactions with cruzain. The designed peptides were synthesized, and their inhibitory potential on cruzain and their trypanocidal and cytotoxic effects in vitro were finally assessed. Results AsCystatin, a potential inhibitor of cysteine proteases, was identified from previously published scientific literature. In silico assays suggested that AsCystatin interacts with key regions of cruzain, and was subsequently produced through heterologous expression, obtaining a protein with a high degree of purity. Next, the inhibition of AsCystatin on the activity of cruzain was assessed, observing that approximately 20 µM of cystatin could inhibit 50% of the catalytic activity of the recombinant enzyme. Based on the in-silico analysis performed previously, original, and modified peptides were designed and tested, which allowed for identifying four peptides with inhibitory capacity on the enzymatic activity of cruzain. Finally, three of these peptides showed trypanocidal activity on epimastigote forms of T. cruzi in in vitro models. Conclusion It was possible to identify AsCystatin and four peptides derived from this protein with inhibitory activity on cruzain, highlighting the trypanocidal effect of these peptides observed in in vitro assays.
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Affiliation(s)
- Jorge Javier Alfonso Ruiz Díaz
- Center for the Development of Scientific Research (CEDIC), Asunción, Paraguay
- Center for the Study of Biomolecules Applied to Health (CEBio), Oswaldo Cruz Foundation (Fiocruz), Fiocruz Rondônia Unit, Porto Velho, RO, Brazil
| | - Ana Fidelina Gómez Garay
- Center for the Development of Scientific Research (CEDIC), Asunción, Paraguay
- Center for the Study of Biomolecules Applied to Health (CEBio), Oswaldo Cruz Foundation (Fiocruz), Fiocruz Rondônia Unit, Porto Velho, RO, Brazil
- International Network for Research and Excellence Knowledge of Western/Eastern Amazon (RED-CONEXAO), Porto Velho, RO, Brazil
| | - Anderson Makoto Kayano
- Center for the Study of Biomolecules Applied to Health (CEBio), Oswaldo Cruz Foundation (Fiocruz), Fiocruz Rondônia Unit, Porto Velho, RO, Brazil
- International Network for Research and Excellence Knowledge of Western/Eastern Amazon (RED-CONEXAO), Porto Velho, RO, Brazil
- Center for Research in Tropical Medicine (CEPEM/SESAU-RO), Porto Velho, RO, Brazil
| | | | - Aleff Ferreira Francisco
- Center for the Study of Biomolecules Applied to Health (CEBio), Oswaldo Cruz Foundation (Fiocruz), Fiocruz Rondônia Unit, Porto Velho, RO, Brazil
- International Network for Research and Excellence Knowledge of Western/Eastern Amazon (RED-CONEXAO), Porto Velho, RO, Brazil
- Laboratory of Biochemistry and Biophysics, Butantan Institute, São Paulo, SP, Brazil
| | | | - Andreimar Martins Soares
- Center for the Study of Biomolecules Applied to Health (CEBio), Oswaldo Cruz Foundation (Fiocruz), Fiocruz Rondônia Unit, Porto Velho, RO, Brazil
- International Network for Research and Excellence Knowledge of Western/Eastern Amazon (RED-CONEXAO), Porto Velho, RO, Brazil
- Laboratory of Biotechnology of Proteins and Bioactive Compounds Applied to Health (LABIOPROT), Oswaldo Cruz Foundation (Fiocruz), Fiocruz Rondônia Unit, Porto Velho, RO, Brazil
- National Institute of Science and Technology in Epidemiology of the Western Amazonia (INCT-EpiAmO), Porto Velho, RO, Brazil
- São Lucas Porto Velho University Center, Porto Velho, RO, Brazi
| | - Celeste Vega
- Center for the Development of Scientific Research (CEDIC), Asunción, Paraguay
| | - Leonardo de Azevedo Calderon
- Center for the Study of Biomolecules Applied to Health (CEBio), Oswaldo Cruz Foundation (Fiocruz), Fiocruz Rondônia Unit, Porto Velho, RO, Brazil
- Department of Medicine, Federal University of Rondônia, Porto Velho, RO, Brazil
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Ramírez-Delgado D, Flores-López CA. Molecular Markers for the Phylogenetic Reconstruction of Trypanosoma cruzi: A Quantitative Review. Pathogens 2025; 14:72. [PMID: 39861033 PMCID: PMC11768369 DOI: 10.3390/pathogens14010072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Trypanosoma cruzi is the parasite responsible for Chagas disease, which has a significant amount of genetic diversification among the species complex. Many efforts are routinely made to characterize the genetic lineages of T. cruzi circulating in a particular geographic area. However, the genetic loci used to typify the genetic lineages of T. cruzi have not been consistent between studies. We report a quantitative analysis of the phylogenetic power that is acquired from the commonly used genetic loci that are employed for the typification of T. cruzi into its current taxonomic nomenclature. Based on three quantitative criteria (the number of phylogenetic informative characters, number of available reference sequences in public repositories, and accessibility to DNA sequences for their use as outgroup sequences), we examine and discuss the most appropriate genetic loci for the genetic typification of T. cruzi. Although the mini-exon gene is by far the locus that has been most widely used, it is not the most appropriate marker for the typification of T. cruzi based on the construction of a resolved phylogenetic tree. Overall, the mitochondrial COII-NDI locus stands out as the best molecular marker for this purpose, followed by the Cytochrome b and the Lathosterol oxidase genes.
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Mata-Santos HA, Sousa Oliveira CV, Feijo DF, Vanzan DF, Vilar-Pereira G, Ramos IP, Carneiro VC, Moreno-Loaiza O, Silverio JC, Lannes-Vieira J, Medei E, Bozza MT, Paiva CN. Heart function enhancement by an Nrf2-activating antioxidant in acute Y-strain Chagas disease, but not in chronic Colombian or Y-strain. PLoS Negl Trop Dis 2024; 18:e0012612. [PMID: 39509468 PMCID: PMC11588235 DOI: 10.1371/journal.pntd.0012612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 11/25/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024] Open
Abstract
Oxidative stress promotes T. cruzi growth and development of chronic Chagas heart dysfunction. However, the literature contains gaps that must be fulfilled, largely due to variations in parasite DTU sources, cell types, mouse strains, and tools to manipulate redox status. We assessed the impact of oxidative environment on parasite burden in cardiomyoblasts and the effects of the Nrf2-inducer COPP on heart function in BALB/c mice infected with either DTU-II Y or DTU-I Colombian T. cruzi strains. Treatment with antioxidants CoPP, apocynin, resveratrol, and tempol reduced parasite burden in cardiomyoblasts H9C2 for both DTUI- and II-strains, while H2O2 increased it. CoPP treatment improved electrical heart function when administered during acute stage of Y-strain infection, coinciding with an overall trend towards increased survival and reduced heart parasite burden. These beneficial effects surpassed those of trypanocidal benznidazole, implying that CoPP directly affects heart physiology. CoPP treatment had beneficial impact on heart systolic function when performed during acute and evaluated during chronic stage. No impact of CoPP on heart parasite burden, electrical, or mechanical function was observed during the chronic stage of Colombian-strain infection, despite previous demonstrations of improvement with other antioxidants. Treatment with CoPP also did not improve heart function of mice chronically infected with Y-strain. Our findings indicate that amastigote growth is responsive to changes in oxidative environment within heart cells regardless of the DTU source, but CoPP influence on heart parasite burden in vivo and heart function is mostly confined to the acute phase. The nature of the antioxidant employed, T. cruzi DTU, and the stage of disease, emerge as crucial factors to consider in heart function studies.
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Affiliation(s)
| | | | - Daniel F. Feijo
- Instituto de Microbiologia Paulo de Goes, UFRJ, Rio de Janeiro, Brazil
| | | | | | - Isalira P. Ramos
- Centro Nacional de Biologia Estrutural e Bioimagem, UFRJ, Rio de Janeiro, Brazil
| | | | | | | | | | - Emiliano Medei
- Institute of Biophysics Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brazil
| | - Marcelo T. Bozza
- Instituto de Microbiologia Paulo de Goes, UFRJ, Rio de Janeiro, Brazil
| | - Claudia N. Paiva
- Instituto de Microbiologia Paulo de Goes, UFRJ, Rio de Janeiro, Brazil
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Vázquez ME, Zabala BA, Mesías AC, Biscari L, Kaufman CD, Alloatti A, Siano F, Picariello G, Corbalán NS, Lenis BA, Toscano MA, Parodi CM, Brandán CMP, Acuña L. Protective Efficacy of the Epitope-Conjugated Antigen N-Tc52/TSkb20 in Mitigating Trypanosoma cruzi Infection through CD8+ T-Cells and IFNγ Responses. Vaccines (Basel) 2024; 12:621. [PMID: 38932350 PMCID: PMC11209121 DOI: 10.3390/vaccines12060621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/02/2024] [Accepted: 05/09/2024] [Indexed: 06/28/2024] Open
Abstract
Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health challenge affecting millions in Latin America and worldwide. Although significant progress has been made in vector control, no vaccine exists to prevent infection or mitigate disease pathogenesis. We developed a rationally designed chimeric protein vaccine, N-Tc52/TSkb20, incorporating immunodominant epitopes from two T. cruzi antigens, the amino-terminal portion of Tc52 and the TSkb20 epitope derived from trans-sialidase. The objectives of this study were to construct and characterize the antigen and evaluate its protective potential in an immunoprophylactic murine model of T. cruzi infection. The N-Tc52/TSkb20 protein was recombinantly expressed in E. coli and its identity was confirmed using mass spectrometry and Western blotting. Immunization with the chimeric protein significantly controlled parasitemia and reduced the heart, colon, and skeletal muscle parasite burdens compared to non-vaccinated mice. Protection was superior to vaccination with the individual parental antigen components. Mechanistically, the vaccine induced potent CD8+ T-cell and IFNγ responses against the incorporated epitopes and a protective IgG antibody profile. A relatively low IL-10 response favored early parasite control. These results validate the promising multi-epitope approach and support the continued development of this type of rational vaccine design strategy against Chagas disease.
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Affiliation(s)
- María Elisa Vázquez
- Unidad de Biotecnología y Protozoarios, Instituto de Patología Experimental “Dr. Miguel Ángel Basombrío”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Salta, Salta A4400, Argentina; (M.E.V.); (B.A.Z.); (A.C.M.); (C.M.P.)
| | - Brenda A. Zabala
- Unidad de Biotecnología y Protozoarios, Instituto de Patología Experimental “Dr. Miguel Ángel Basombrío”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Salta, Salta A4400, Argentina; (M.E.V.); (B.A.Z.); (A.C.M.); (C.M.P.)
| | - Andrea C. Mesías
- Unidad de Biotecnología y Protozoarios, Instituto de Patología Experimental “Dr. Miguel Ángel Basombrío”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Salta, Salta A4400, Argentina; (M.E.V.); (B.A.Z.); (A.C.M.); (C.M.P.)
| | - Lucia Biscari
- Instituto de Inmunología Clínica y Experimental de Rosario, IDICER—CONICET—UNR, Rosario 2000, Argentina; (L.B.); (C.D.K.); (A.A.)
| | - Cintia D. Kaufman
- Instituto de Inmunología Clínica y Experimental de Rosario, IDICER—CONICET—UNR, Rosario 2000, Argentina; (L.B.); (C.D.K.); (A.A.)
| | - Andrés Alloatti
- Instituto de Inmunología Clínica y Experimental de Rosario, IDICER—CONICET—UNR, Rosario 2000, Argentina; (L.B.); (C.D.K.); (A.A.)
| | - Francesco Siano
- Istituto di Scienze dell’ Alimentazione—Consiglio Nazionale delle Ricerche (CNR), 83100 Avellino, Italy; (F.S.); (G.P.)
| | - Gianluca Picariello
- Istituto di Scienze dell’ Alimentazione—Consiglio Nazionale delle Ricerche (CNR), 83100 Avellino, Italy; (F.S.); (G.P.)
| | - Natalia S. Corbalán
- Facultad de Ciencias Naturales, Universidad Nacional de Salta, Salta A4400, Argentina;
| | - Bladimiro A. Lenis
- Unidad de Conocimiento Traslacional, Hospital Arturo Oñativia, Salta A4400, Argentina; (B.A.L.); (M.A.T.)
| | - Marta A. Toscano
- Unidad de Conocimiento Traslacional, Hospital Arturo Oñativia, Salta A4400, Argentina; (B.A.L.); (M.A.T.)
| | - Cecilia M. Parodi
- Unidad de Biotecnología y Protozoarios, Instituto de Patología Experimental “Dr. Miguel Ángel Basombrío”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Salta, Salta A4400, Argentina; (M.E.V.); (B.A.Z.); (A.C.M.); (C.M.P.)
| | - Cecilia M. Pérez Brandán
- Unidad de Biotecnología y Protozoarios, Instituto de Patología Experimental “Dr. Miguel Ángel Basombrío”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Salta, Salta A4400, Argentina; (M.E.V.); (B.A.Z.); (A.C.M.); (C.M.P.)
| | - Leonardo Acuña
- Unidad de Biotecnología y Protozoarios, Instituto de Patología Experimental “Dr. Miguel Ángel Basombrío”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Salta, Salta A4400, Argentina; (M.E.V.); (B.A.Z.); (A.C.M.); (C.M.P.)
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Guntaka S, Lin A, Bae S, Vaysblat M, Pierce M. An Uncommon Presentation of Unstable Ventricular Tachycardia: Raising Awareness for Early Recognition of Chagas Disease. Cureus 2024; 16:e61189. [PMID: 38939252 PMCID: PMC11210336 DOI: 10.7759/cureus.61189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2024] [Indexed: 06/29/2024] Open
Abstract
Chagas disease (CD), caused by Trypanosoma cruzi, is a leading cause of cardiomyopathy in Latin America that can lead to heart failure, arrhythmias, and sudden cardiac death (SCD). We present a case of a 71-year-old female from El Salvador with symptomatic ventricular tachycardia (VT) requiring emergent cardioversion and implantable cardioverter-defibrillator (ICD) due to CD. Diagnostic evaluation is limited and unclear in cases of chronic disease. Treatment involves antiparasitic therapy, heart failure management, and arrhythmia prevention. With growing numbers of cases in the US and limited treatment options, we highlight the need for timely recognition and intervention to reduce the burden of CD.
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Affiliation(s)
| | - Allan Lin
- Internal Medicine, Northwell Health, Manhasset, USA
| | - Suhwoo Bae
- Internal Medicine, Northwell Health, Manhasset, USA
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Berhe H, Kumar Cinthakunta Sridhar M, Zerihun M, Qvit N. The Potential Use of Peptides in the Fight against Chagas Disease and Leishmaniasis. Pharmaceutics 2024; 16:227. [PMID: 38399281 PMCID: PMC10892537 DOI: 10.3390/pharmaceutics16020227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 12/28/2023] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
Chagas disease and leishmaniasis are both neglected tropical diseases that affect millions of people around the world. Leishmaniasis is currently the second most widespread vector-borne parasitic disease after malaria. The World Health Organization records approximately 0.7-1 million newly diagnosed leishmaniasis cases each year, resulting in approximately 20,000-30,000 deaths. Also, 25 million people worldwide are at risk of Chagas disease and an estimated 6 million people are infected with Trypanosoma cruzi. Pentavalent antimonials, amphotericin B, miltefosine, paromomycin, and pentamidine are currently used to treat leishmaniasis. Also, nifurtimox and benznidazole are two drugs currently used to treat Chagas disease. These drugs are associated with toxicity problems such as nephrotoxicity and cardiotoxicity, in addition to resistance problems. As a result, the discovery of novel therapeutic agents has emerged as a top priority and a promising alternative. Overall, there is a need for new and effective treatments for Chagas disease and leishmaniasis, as the current drugs have significant limitations. Peptide-based drugs are attractive due to their high selectiveness, effectiveness, low toxicity, and ease of production. This paper reviews the potential use of peptides in the treatment of Chagas disease and leishmaniasis. Several studies have demonstrated that peptides are effective against Chagas disease and leishmaniasis, suggesting their use in drug therapy for these diseases. Overall, peptides have the potential to be effective therapeutic agents against Chagas disease and leishmaniasis, but more research is needed to fully investigate their potential.
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Affiliation(s)
| | | | | | - Nir Qvit
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel; (H.B.); (M.K.C.S.); (M.Z.)
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Madeira RP, Meneghetti P, Lozano N, Namiyama GM, Pereira-Chioccola VL, Torrecilhas AC. Exploring Peripheral Blood-Derived Extracellular Vesicles as Biomarkers: Implications for Chronic Chagas Disease with Viral Infection or Transplantation. Microorganisms 2024; 12:116. [PMID: 38257943 PMCID: PMC10818975 DOI: 10.3390/microorganisms12010116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 12/30/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Extracellular vesicles (EVs) are lipid bilayer envelopes that encapsulate cell-specific cargo, rendering them promising biomarkers for diverse diseases. Chagas disease, caused by the parasite Trypanosoma cruzi, poses a significant global health burden, transcending its initial epicenter in Latin America to affect individuals in Europe, Asia, and North America. In this study, we aimed to characterize circulating EVs derived from patients with chronic Chagas disease (CCD) experiencing a reactivation of acute symptoms. Blood samples collected in EDTA were processed to isolate plasma and subsequently subjected to ultracentrifugation for particle isolation and purification. The EVs were characterized using a nanoparticle tracking analysis and enzyme-linked immunosorbent assay (ELISA). Our findings revealed distinctive differences in the size, concentration, and composition of EVs between immunosuppressed patients and those with CCD. Importantly, these EVs play a critical role in the pathophysiology of Chagas disease and demonstrate significant potential as biomarkers in the chronic phase of the disease. Overall, our findings support the potential utility of the CL-ELISA assay as a specific sensitive tool for detecting circulating EVs in chronic Chagasic patients, particularly those with recurrent infection following an immunosuppressive treatment or with concurrent HIV and Chagas disease. Further investigations are warranted to identify and validate the specific antigens or biomarkers responsible for the observed reactivity in these patient groups, which may have implications for diagnosis, the monitoring of treatment, and prognosis.
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Affiliation(s)
- Rafael Pedro Madeira
- Disciplina de Infectologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (R.P.M.); (N.L.)
- Departamento de Ciências Farmacêuticas, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema 09913-030, Brazil;
| | - Paula Meneghetti
- Departamento de Ciências Farmacêuticas, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema 09913-030, Brazil;
- Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil
| | - Nicholy Lozano
- Disciplina de Infectologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (R.P.M.); (N.L.)
- Departamento de Ciências Farmacêuticas, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema 09913-030, Brazil;
| | - Gislene M. Namiyama
- Electron Microscopy Laboratory, Adolfo Lutz Institute, São Paulo 01246-900, Brazil;
| | - Vera Lucia Pereira-Chioccola
- Laboratório de Biologia Molecular de Fungos e Parasitas, Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil
| | - Ana Claudia Torrecilhas
- Departamento de Ciências Farmacêuticas, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema 09913-030, Brazil;
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9
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Francisco AF, Sousa GR, Vaughan M, Langston H, Khan A, Jayawardhana S, Taylor MC, Lewis MD, Kelly JM. Cardiac Abnormalities in a Predictive Mouse Model of Chagas Disease. Pathogens 2023; 12:1364. [PMID: 38003828 PMCID: PMC10674564 DOI: 10.3390/pathogens12111364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/09/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
Chronic Chagas cardiomyopathy (CCC) results from infection with the protozoan parasite Trypanosoma cruzi and is a prevalent cause of heart disease in endemic countries. We previously found that cardiac fibrosis can vary widely in C3H/HeN mice chronically infected with T. cruzi JR strain, mirroring the spectrum of heart disease in humans. In this study, we examined functional cardiac abnormalities in this host:parasite combination to determine its potential as an experimental model for CCC. We utilised electrocardiography (ECG) to monitor T. cruzi-infected mice and determine whether ECG markers could be correlated with cardiac function abnormalities. We found that the C3H/HeN:JR combination frequently displayed early onset CCC indicators, such as sinus bradycardia and right bundle branch block, as well as prolonged PQ, PR, RR, ST, and QT intervals in the acute stage. Our model exhibited high levels of cardiac inflammation and enhanced iNOS expression in the acute stage, but denervation did not appear to have a role in pathology. These results demonstrate the potential of the C3H/HeN:JR host:parasite combination as a model for CCC that could be used for screening new compounds targeted at cardiac remodelling and for examining the potential of antiparasitic drugs to prevent or alleviate CCC development and progression.
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Affiliation(s)
- Amanda Fortes Francisco
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Giovane R. Sousa
- Harvard Medical School, Section on Immunobiology, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA
| | - Mhairi Vaughan
- Research Department of Haematology, Cancer Institute, Faculty of Medical Sciences, University College London, London WC1E 6DD, UK
| | - Harry Langston
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Archie Khan
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Shiromani Jayawardhana
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Martin C. Taylor
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Michael D. Lewis
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - John M. Kelly
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
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Tunali V, Korkmaz M. Emerging and Re-Emerging Parasitic Infections of the Central Nervous System (CNS) in Europe. Infect Dis Rep 2023; 15:679-699. [PMID: 37987400 PMCID: PMC10660548 DOI: 10.3390/idr15060062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 10/12/2023] [Accepted: 10/20/2023] [Indexed: 11/22/2023] Open
Abstract
In a rapidly evolving global landscape characterized by increased international travel, migration, and ecological shifts, this study sheds light on the emergence of protozoal and helminthic infections targeting the central nervous system (CNS) within Europe. Despite being traditionally associated with tropical regions, these infections are progressively becoming more prevalent in non-endemic areas. By scrutinizing the inherent risks, potential outcomes, and attendant challenges, this study underscores the intricate interplay between diagnostic limitations, susceptibility of specific population subsets, and the profound influence of climate fluctuations. The contemporary interconnectedness of societies serves as a conduit for introducing and establishing these infections, warranting comprehensive assessment. This study emphasizes the pivotal role of heightened clinician vigilance, judicious public health interventions, and synergistic research collaborations to mitigate the potential consequences of these infections. Though rare, their profound impact on morbidity and mortality underscores the collective urgency required to safeguard the neurological well-being of the European populace. Through this multifaceted approach, Europe can effectively navigate the complex terrain posed with these emergent infections.
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Affiliation(s)
- Varol Tunali
- Department of Parasitology, Faculty of Medicine, Manisa Celal Bayar University, 45030 Manisa, Turkey
- Department of Emergency Medicine, Izmir Metropolitan Municipality Eşrefpaşa Hospital, 35170 Izmir, Turkey
| | - Metin Korkmaz
- Department of Parasitology, Faculty of Medicine, Ege University, 35100 Izmir, Turkey;
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11
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Gomes DC, Medeiros TS, Alves Pereira EL, da Silva JFO, de Freitas Oliveira JW, Fernandes-Pedrosa MDF, de Sousa da Silva M, da Silva-Júnior AA. From Benznidazole to New Drugs: Nanotechnology Contribution in Chagas Disease. Int J Mol Sci 2023; 24:13778. [PMID: 37762080 PMCID: PMC10530915 DOI: 10.3390/ijms241813778] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/31/2023] [Accepted: 08/05/2023] [Indexed: 09/29/2023] Open
Abstract
Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi. Benznidazole and nifurtimox are the two approved drugs for their treatment, but both drugs present side effects and efficacy problems, especially in the chronic phase of this disease. Therefore, new molecules have been tested with promising results aiming for strategic targeting action against T. cruzi. Several studies involve in vitro screening, but a considerable number of in vivo studies describe drug bioavailability increment, drug stability, toxicity assessment, and mainly the efficacy of new drugs and formulations. In this context, new drug delivery systems, such as nanotechnology systems, have been developed for these purposes. Some nanocarriers are able to interact with the immune system of the vertebrate host, modulating the immune response to the elimination of pathogenic microorganisms. In this overview of nanotechnology-based delivery strategies for established and new antichagasic agents, different strategies, and limitations of a wide class of nanocarriers are explored, as new perspectives in the treatment and monitoring of Chagas disease.
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Affiliation(s)
- Daniele Cavalcante Gomes
- Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte-UFRN, Natal 59012-570, Brazil; (D.C.G.); (T.S.M.); (E.L.A.P.); (J.F.O.d.S.); (M.d.F.F.-P.)
| | - Thayse Silva Medeiros
- Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte-UFRN, Natal 59012-570, Brazil; (D.C.G.); (T.S.M.); (E.L.A.P.); (J.F.O.d.S.); (M.d.F.F.-P.)
| | - Eron Lincoln Alves Pereira
- Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte-UFRN, Natal 59012-570, Brazil; (D.C.G.); (T.S.M.); (E.L.A.P.); (J.F.O.d.S.); (M.d.F.F.-P.)
| | - João Felipe Oliveira da Silva
- Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte-UFRN, Natal 59012-570, Brazil; (D.C.G.); (T.S.M.); (E.L.A.P.); (J.F.O.d.S.); (M.d.F.F.-P.)
| | - Johny W. de Freitas Oliveira
- Immunoparasitology Laboratory, Department of Clinical and Toxicological Analysis, Centre of Health Sciences, Federal University of Rio Grande do Norte-UFRN, Natal 59012-570, Brazil; (J.W.d.F.O.); (M.d.S.d.S.)
| | - Matheus de Freitas Fernandes-Pedrosa
- Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte-UFRN, Natal 59012-570, Brazil; (D.C.G.); (T.S.M.); (E.L.A.P.); (J.F.O.d.S.); (M.d.F.F.-P.)
| | - Marcelo de Sousa da Silva
- Immunoparasitology Laboratory, Department of Clinical and Toxicological Analysis, Centre of Health Sciences, Federal University of Rio Grande do Norte-UFRN, Natal 59012-570, Brazil; (J.W.d.F.O.); (M.d.S.d.S.)
| | - Arnóbio Antônio da Silva-Júnior
- Laboratory of Pharmaceutical Technology and Biotechnology, Department of Pharmacy, Federal University of Rio Grande do Norte-UFRN, Natal 59012-570, Brazil; (D.C.G.); (T.S.M.); (E.L.A.P.); (J.F.O.d.S.); (M.d.F.F.-P.)
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Jimenez A, Winokur EJ. Chagas Disease Cardiomyopathy. Dimens Crit Care Nurs 2023; 42:202-210. [PMID: 37219474 DOI: 10.1097/dcc.0000000000000590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023] Open
Abstract
Chagas disease is a prominent neglected tropical disease endemic to many countries in Latin America. Cardiomyopathy is the most serious manifestation due to the severity and complications of heart failure. As a result of expanded immigration and globalization, there is an increased number of patients with Chagas cardiomyopathy who are being admitted to hospitals in the United States. It is imperative as a critical care nurse to be educated on the nature of Chagas cardiomyopathy as it differs from the more commonly seen ischemic and nonischemic forms. This article provides an overview of the clinical course, management, and treatment options of Chagas cardiomyopathy.
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Alhassani Z, Hennawi HA, Sevella P, Mena CS, Coppola K. Chagas disease-induced ventricular tachycardia: A case report. Glob Cardiol Sci Pract 2023; 2023:e202303. [PMID: 36890840 PMCID: PMC9988298 DOI: 10.21542/gcsp.2023.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/10/2023] [Indexed: 02/08/2023] Open
Abstract
Chagas disease is a protozoal infection caused by Trypanosoma cruzi (T. cruzi) that can affect many organ systems. Chagas cardiomyopathy tends to affect 30% of infected individuals. Cardiac manifestations include myocardial fibrosis, conduction defects, cardiomyopathy, ventricular tachycardia, and sudden cardiac death. In this report, we discuss a 51-year-old male who presented with recurrent episodes of non-sustained ventricular tachycardia refractory to medical therapy.
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Affiliation(s)
- Zaineb Alhassani
- Department of Internal Medicine, Jefferson Abington Hospital, Abington, PA, USA
| | - Hussam Al Hennawi
- Department of Internal Medicine, Jefferson Abington Hospital, Abington, PA, USA
| | - Prerana Sevella
- Department of Internal Medicine, Jefferson Abington Hospital, Abington, PA, USA
| | | | - Kathleen Coppola
- Department of Internal Medicine, Jefferson Abington Hospital, Abington, PA, USA
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14
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Montalvo-Ocotoxtle IG, Rojas-Velasco G, Rodríguez-Morales O, Arce-Fonseca M, Baeza-Herrera LA, Arzate-Ramírez A, Meléndez-Ramírez G, Manzur-Sandoval D, Lara-Romero ML, Reyes-Ortega A, Espinosa-González P, Palacios-Rosas E. Chagas Heart Disease: Beyond a Single Complication, from Asymptomatic Disease to Heart Failure. J Clin Med 2022; 11:7262. [PMID: 36555880 PMCID: PMC9784121 DOI: 10.3390/jcm11247262] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Chagas cardiomyopathy (CC), caused by the protozoan Trypanosoma cruzi, is an important cause of cardiovascular morbidity and mortality in developing countries. It is estimated that 6 to 7 million people worldwide are infected, and it is predicted that it will be responsible for 200,000 deaths by 2025. The World Health Organization (WHO) considers Chagas disease (CD) as a Neglected Tropical Disease (NTD), which must be acknowledged and detected in time, as it remains a clinical and diagnostic challenge in both endemic and non-endemic regions and at different levels of care. The literature on CC was analyzed by searching different databases (Medline, Cochrane Central, EMBASE, PubMed, Google Scholar, EBSCO) from 1968 until October 2022. Multicenter and bioinformatics trials, systematic and bibliographic reviews, international guidelines, and clinical cases were included. The reference lists of the included papers were checked. No linguistic restrictions or study designs were applied. This review is intended to address the current incidence and prevalence of CD and to identify the main pathogenic mechanisms, clinical presentation, and diagnosis of CC.
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Affiliation(s)
- Isis G. Montalvo-Ocotoxtle
- Cardiovascular Critical Care Unit, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Gustavo Rojas-Velasco
- Cardiovascular Critical Care Unit, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Olivia Rodríguez-Morales
- Department of Molecular Biology, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Minerva Arce-Fonseca
- Department of Molecular Biology, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Luis A. Baeza-Herrera
- Cardiovascular Critical Care Unit, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Arturo Arzate-Ramírez
- Cardiovascular Critical Care Unit, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Gabriela Meléndez-Ramírez
- Magnetic Resonance Imaging Department, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Daniel Manzur-Sandoval
- Cardiovascular Critical Care Unit, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Mayra L. Lara-Romero
- Academic Department of Health Sciences, School of Sciences, Universidad de las Américas Puebla, Ex Hacienda Sta. Catarina Mártir S/N. San Andrés Cholula, Puebla 72810, Mexico
| | - Antonio Reyes-Ortega
- Cardiovascular Critical Care Unit, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Patricia Espinosa-González
- Cardiovascular Critical Care Unit, National Institute of Cardiology “Ignacio Chávez”, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Erika Palacios-Rosas
- Academic Department of Health Sciences, School of Sciences, Universidad de las Américas Puebla, Ex Hacienda Sta. Catarina Mártir S/N. San Andrés Cholula, Puebla 72810, Mexico
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15
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de Lederkremer RM, Giorgi ME, Marino C. The α-Galactosyl Carbohydrate Epitope in Pathogenic Protozoa. ACS Infect Dis 2022; 8:2207-2222. [PMID: 36083842 DOI: 10.1021/acsinfecdis.2c00370] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The α-gal epitope, which refers to the carbohydrate α-d-Galp-(1 → 3)-β-d-Galp-(1 → 4)-d-GlcNAc-R, was first described in the glycoconjugates of mammals other than humans. Evolution caused a mutation that resulted in the inactivation of the α-1,3-galactosyltransferase gene. For that reason, humans produce antibodies against α-d-Galp containing glycoproteins and glycolipids of other species. We summarize here the glycoconjugates with α-d-Galp structures in Trypanosoma, Leishmania, and Plasmodium pathogenic protozoa. These were identified in infective stages of Trypanosoma cruzi and in Plasmodium sporozoites. In Leishmania, α-d-Galp is linked differently in the glycans of glycoinositolphospholipids (GIPLs). Chemically synthesized neoglycoconjugates have been proposed as diagnostic tools and as antigens for vaccines. Several syntheses reported for the α-gal trisaccharide, also called the Galili epitope, and the glycans of GIPLs found in Leishmania, the preparation of neoglycoconjugates, and the studies in which they were involved are also included in this Review.
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Affiliation(s)
- Rosa M de Lederkremer
- CIHIDECAR, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón II, Ciudad Universitaria, 1428Buenos Aires, Argentina
| | - María Eugenia Giorgi
- CIHIDECAR, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón II, Ciudad Universitaria, 1428Buenos Aires, Argentina
| | - Carla Marino
- CIHIDECAR, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón II, Ciudad Universitaria, 1428Buenos Aires, Argentina
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de Souza-Silva TG, Gollob KJ, Dutra WO. T-cell receptor variable region usage in Chagas disease: A systematic review of experimental and human studies. PLoS Negl Trop Dis 2022; 16:e0010546. [PMID: 36107855 PMCID: PMC9477334 DOI: 10.1371/journal.pntd.0010546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
T cells recognize their ligand, the peptide major histocompatibility complex (MHC), via the T-cell receptor (TCR), which is composed of covalently linked α and β or γ and δ chains. This recognition is critical for T-cell ontogeny and controls the selection, activation, and function of T lymphocytes. Specific TCR αβ variable regions have been associated with immunopathogenesis of Chagas disease. Here, we present a systematic review that compiles experimental in vivo and human data regarding the preferential expression of variable alpha (Vα) and variable beta (Vβ) chain regions in Trypanosoma cruzi infection. The original studies indexed in PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. The analysis showed that expression of TCR Vα subfamilies were evaluated in one human study, and, unlike TCR Vβ, TCR Vα presented a more restricted usage. Despite the great variability in the usage of TCR Vβ regions in human Chagas disease, a down-regulation of TCR Vβ5 expression by T cells from patients in the acute phase of the disease was shown. Opposingly, this TCR region was found overly expressed in CD4+ T cells from chronic Chagas patients. It was also demonstrated that murine Vβ9+ T cells derived from nonlymphoid organs of T. cruzi-infected animals had a modulatory profile, while splenic Vβ9+ T cells produced inflammatory cytokines, indicating that although they display the same TCR Vβ region usage, these cells are functionally distinct. Despite the limitations of few papers and year of publication of the studies, compiling the data derived from them reveals that further investigation of TCR usage will point to their potential role in protective or pathogenic responses, as biomarkers of disease progression, and in the search for dominant peptides potentially useful for the development of vaccines or therapies. Chagas disease is a neglected tropical disease, caused by infection with Trypanosoma cruzi. Differential expression of certain T-cell receptor (TCR) variable regions has been associated with the immunopathogenesis of Chagas disease. Here, we present a systematic review that compiled experimental in vivo and human data regarding the preferential expression of TCR alpha and beta chain variable regions in Chagas disease. The original studies indexed in the PubMed/Medline, Scopus, and Web of Science databases were screened according to the PRISMA strategy. Despite the great variability in the use of TCR Vβ in T. cruzi infection, the outcomes indicate that there is a down-regulation of TCR Vβ5 expression in T cells from patients in the acute phase of Chagas disease. However, this region is preferentially expressed by CD4+ T cells from chronic Chagas patients. Additionally, it has been demonstrated that murine Vβ9+ T cells derived from nonlymphoid organs displayed a modulatory profile, while splenic Vβ9+ T cells produced inflammatory cytokines, indicating that although they express the same TCR Vβ region, these cells are functionally distinct. Information on TCR expression, specificity and function have critical impact on vaccine design.
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Affiliation(s)
- Thaiany Goulart de Souza-Silva
- Institute of Biological Sciences, Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Kenneth J. Gollob
- Hospital Israelita Albert Einstein, São Paulo, Brazil
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Belo Horizonte, Minas Gerais, Brazil
| | - Walderez O. Dutra
- Institute of Biological Sciences, Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais, Belo Horizonte, Minas Gerais, Brazil
- * E-mail:
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Di Bello E, Noce B, Fioravanti R, Zwergel C, Valente S, Rotili D, Fianco G, Trisciuoglio D, Mourão MM, Sales P, Lamotte S, Prina E, Späth GF, Häberli C, Keiser J, Mai A. Effects of Structurally Different HDAC Inhibitors against Trypanosoma cruzi, Leishmania, and Schistosoma mansoni. ACS Infect Dis 2022; 8:1356-1366. [PMID: 35732073 PMCID: PMC9274761 DOI: 10.1021/acsinfecdis.2c00232] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
![]()
Neglected tropical
diseases (NTDs), including trypanosomiasis,
leishmaniasis, and schistosomiasis, result in a significant burden
in terms of morbidity and mortality worldwide every year. Current
antiparasitic drugs suffer from several limitations such as toxicity,
no efficacy toward all of the forms of the parasites’ life
cycle, and/or induction of resistance. Histone-modifying enzymes play
a crucial role in parasite growth and survival; thus, the use of epigenetic
drugs has been suggested as a strategy for the treatment of NTDs.
We tested structurally different HDACi 1–9, chosen from our in-house library or newly synthesized,
against Trypanosoma cruzi,
Leishmania spp, and Schistosoma mansoni. Among them, 4 emerged as the most potent against all
of the tested parasites, but it was too toxic against host cells,
hampering further studies. The retinoic 2′-aminoanilide 8 was less potent than 4 in all parasitic assays,
but as its toxicity is considerably lower, it could be the starting
structure for further development. In T. cruzi, compound 3 exhibited a single-digit micromolar inhibition of parasite
growth combined with moderate toxicity. In S. mansoni, 4’s close analogs 17–20 were tested in new transformed schistosomula (NTS) and
adult worms displaying high death induction against both parasite
forms. Among them, 17 and 19 exhibited very
low toxicity in human retinal pigment epithelial (RPE) cells, thus
being promising compounds for further optimization.
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Affiliation(s)
- Elisabetta Di Bello
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Beatrice Noce
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Giulia Fianco
- Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185 Rome, Italy
| | - Daniela Trisciuoglio
- Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185 Rome, Italy
| | - Marina M Mourão
- Instituto René Rachou, Fundação Oswaldo Cruz, Avenida Augusto de Lima, 1715, 30190-002 Belo Horizonte, Brazil
| | - Policarpo Sales
- Instituto René Rachou, Fundação Oswaldo Cruz, Avenida Augusto de Lima, 1715, 30190-002 Belo Horizonte, Brazil
| | - Suzanne Lamotte
- Institut Pasteur, Université Paris Cité, INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, 25-28 Rue du Docteur Roux, 75015 Paris, France
| | - Eric Prina
- Institut Pasteur, Université Paris Cité, INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, 25-28 Rue du Docteur Roux, 75015 Paris, France
| | - Gerald F Späth
- Institut Pasteur, Université Paris Cité, INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, 25-28 Rue du Docteur Roux, 75015 Paris, France
| | - Cécile Häberli
- Swiss Tropical and Public Health Institute, 4002 Allschwil, Switzerland.,University of Basel, Peterspl. 1, 4001 Basel, Switzerland
| | - Jennifer Keiser
- Swiss Tropical and Public Health Institute, 4002 Allschwil, Switzerland.,University of Basel, Peterspl. 1, 4001 Basel, Switzerland
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.,Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
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18
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Pinto BF, Medeiros NI, Teixeira-Carvalho A, Fiuza JA, Eloi-Santos SM, Nunes MCP, Silva SA, Fontes-Cal TCM, Belchior-Bezerra M, Dutra WO, Correa-Oliveira R, Gomes JAS. Modulation of Regulatory T Cells Activity by Distinct CD80 and CD86 Interactions With CD28/CTLA-4 in Chagas Cardiomyopathy. Front Cardiovasc Med 2022; 9:750876. [PMID: 35665256 PMCID: PMC9162138 DOI: 10.3389/fcvm.2022.750876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 04/08/2022] [Indexed: 11/16/2022] Open
Abstract
Chagas cardiomyopathy is the symptomatic cardiac clinical form (CARD) of the chronic phase of Chagas disease caused by Trypanosoma cruzi infection. It was described as the most fibrosing cardiomyopathies, affecting approximately 30% of patients during the chronic phase. Other less frequent symptomatic clinical forms have also been described. However, most patients who progress to the chronic form develop the indeterminate clinical form (IND), may remain asymptomatic for life, or develop some cardiac damage. Some mechanisms involved in the etiology of the clinical forms of Chagas disease have been investigated. To characterize the contribution of CD80 and CD86 co-stimulatory molecules in the activation of different CD4+ (Th1, Th2, Th17, and Treg) and CD8+ T lymphocyte subsets, we used blocking antibodies for CD80 and CD86 receptors of peripheral blood mononuclear cells (PBMC) in cultures with T. cruzi antigens from non-infected (NI), IND, and CARD individuals. We demonstrated a higher frequency of CD8+ CD25+ T lymphocytes and CD8+ Treg cells after anti-CD80 antibody blockade only in the CARD group. In contrast, a lower frequency of CD4+ Treg lymphocytes after anti-CD86 antibody blockade was found only in IND patients. A higher frequency of CD4+ Treg CD28+ lymphocytes, as well as an association between CD4+ Treg lymphocytes and CD28+ expression on CD4+ Treg cells in the CARD group, but not in IND patients, and once again only after anti-CD80 antibody blockade, was observed. We proposed that Treg cells from IND patients could be activated via CD86-CTLA-4 interaction, leading to modulation of the immune response only in asymptomatic patients with Chagas disease, while CD80 may be involved in the proliferation control of T CD8+ lymphocytes, as also in the modulation of regulatory cell activation via CD28 receptor. For the first time, our data highlight the role of CD80 in modulation of Treg lymphocytes activation in patients with CARD, highlighting a key molecule in the development of Chagas cardiomyopathy.
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Affiliation(s)
- Bruna F. Pinto
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Nayara I. Medeiros
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Instituto René Rachou, Fundação Oswaldo Cruz–FIOCRUZ, Belo Horizonte, Brazil
| | | | - Jacqueline A. Fiuza
- Instituto René Rachou, Fundação Oswaldo Cruz–FIOCRUZ, Belo Horizonte, Brazil
| | | | - Maria C. P. Nunes
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Silvana A. Silva
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Tereza C. M. Fontes-Cal
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mayara Belchior-Bezerra
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Walderez O. Dutra
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Instituto Nacional de Ciência e Tecnologia Doenças Tropicais, Belo Horizonte, Brazil
| | - Rodrigo Correa-Oliveira
- Instituto René Rachou, Fundação Oswaldo Cruz–FIOCRUZ, Belo Horizonte, Brazil
- Instituto Nacional de Ciência e Tecnologia Doenças Tropicais, Belo Horizonte, Brazil
| | - Juliana A. S. Gomes
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- *Correspondence: Juliana A. S. Gomes,
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Lima ACGB, Formiga MF, Giollo LT, da Silva ML, da Silva VZM, Otto MEB, Chiappa GR, Cipriano G. Arterial stiffness and pulse wave morphology in Chagas heart failure: insights from noninvasive applanation tonometry. J Cardiovasc Med (Hagerstown) 2022; 23:e36-e38. [PMID: 34839319 DOI: 10.2459/jcm.0000000000001287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
| | | | | | | | - Vinicius Z M da Silva
- University of Brasília, Distrito Federal
- University Center of Anapólis (UniEVANGÉLICA), Goiás, Brazil
| | | | - Gaspar R Chiappa
- University of Brasília, Distrito Federal
- University Center of Anapólis (UniEVANGÉLICA), Goiás, Brazil
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20
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KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity. Life (Basel) 2021; 11:life11101037. [PMID: 34685408 PMCID: PMC8540442 DOI: 10.3390/life11101037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/21/2021] [Accepted: 09/28/2021] [Indexed: 11/17/2022] Open
Abstract
Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.
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21
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Rodrigues da Cunha GM, Azevedo MA, Nogueira DS, Clímaco MDC, Valencia Ayala E, Jimenez Chunga JA, La Valle RJY, da Cunha Galvão LM, Chiari E, Brito CRN, Soares RP, Nogueira PM, Fujiwara RT, Gazzinelli R, Hincapie R, Chaves CS, Oliveira FMS, Finn MG, Marques AF. α-Gal immunization positively impacts Trypanosoma cruzi colonization of heart tissue in a mouse model. PLoS Negl Trop Dis 2021; 15:e0009613. [PMID: 34314435 PMCID: PMC8345864 DOI: 10.1371/journal.pntd.0009613] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 08/06/2021] [Accepted: 06/30/2021] [Indexed: 01/03/2023] Open
Abstract
Chagas disease, caused by the parasite Trypanosoma cruzi, is considered endemic in more than 20 countries but lacks both an approved vaccine and limited treatment for its chronic stage. Chronic infection is most harmful to human health because of long-term parasitic infection of the heart. Here we show that immunization with a virus-like particle vaccine displaying a high density of the immunogenic α-Gal trisaccharide (Qβ-αGal) induced several beneficial effects concerning acute and chronic T. cruzi infection in α1,3-galactosyltransferase knockout mice. Approximately 60% of these animals were protected from initial infection with high parasite loads. Vaccinated animals also produced high anti-αGal IgG antibody titers, improved IFN-γ and IL-12 cytokine production, and controlled parasitemia in the acute phase at 8 days post-infection (dpi) for the Y strain and 22 dpi for the Colombian strain. In the chronic stage of infection (36 and 190 dpi, respectively), all of the vaccinated group survived, showing significantly decreased heart inflammation and clearance of amastigote nests from the heart tissue.
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Affiliation(s)
| | - Maíra Araújo Azevedo
- Universidade Federal de Minas Gerais, Departamento de Parasitologia, Belo Horizonte, Brazil
| | - Denise Silva Nogueira
- Universidade Federal de Minas Gerais, Departamento de Parasitologia, Belo Horizonte, Brazil
| | | | | | - Juan Atilio Jimenez Chunga
- Universidad Nacional Mayor de San Marcos, Faculdad de Ciencias Biologicas, Escuela Profesional de Microbiología y Parasitología—Laboratorio de Parasitología en Fauna Silvestre y Zoonosis, Lima, Peru
| | - Raul Jesus Ynocente La Valle
- Universidad Nacional Mayor de San Marcos, Faculdad de Ciencias Biologicas, Escuela Profesional de Microbiología y Parasitología—Laboratorio de Parasitología en Fauna Silvestre y Zoonosis, Lima, Peru
| | | | - Egler Chiari
- Universidade Federal de Minas Gerais, Departamento de Parasitologia, Belo Horizonte, Brazil
| | - Carlos Ramon Nascimento Brito
- Universidade Federal do Rio Grande do Norte—Centro de Ciências da Saúde—Departamento de Análises Clínicas e Toxicológicas, Natal, Brazil
| | | | | | | | - Ricardo Gazzinelli
- Universidade Federal de Minas Gerais, Departamento de Parasitologia, Belo Horizonte, Brazil
- Instituto René Rachou/FIOCRUZ–MG, Belo Horizonte, Brazil
| | - Robert Hincapie
- School of Chemistry and Biochemistry, School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | - Carlos-Sanhueza Chaves
- School of Chemistry and Biochemistry, School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America
| | | | - M. G. Finn
- School of Chemistry and Biochemistry, School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, United States of America
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22
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Rincón-Acevedo CY, Parada-García AS, Olivera MJ, Torres-Torres F, Zuleta-Dueñas LP, Hernández C, Ramírez JD. Clinical and Epidemiological Characterization of Acute Chagas Disease in Casanare, Eastern Colombia, 2012-2020. Front Med (Lausanne) 2021; 8:681635. [PMID: 34368188 PMCID: PMC8343227 DOI: 10.3389/fmed.2021.681635] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/29/2021] [Indexed: 12/29/2022] Open
Abstract
Background: Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is considered a public health problem in Latin America. In Colombia, it affects more than 437,000 inhabitants, mainly in Casanare, an endemic region with eco-epidemiological characteristics that favor its transmission. The objective of this study was to describe the clinical and epidemiological characteristics of the cases of acute CD in Casanare, eastern Colombia, in the period 2012–2020. Methods: In the present study, 103 medical records of confirmed cases of acute CD were reviewed. The departmental/national incidence and fatality were compared by year; the climatological data of mean temperature, relative humidity, and precipitation per year were reviewed and plotted at IDEAM (Colombian Meteorology Institute) concerning the number of cases of acute CD per month, and it was compared with the frequency of triatomines collected in infested houses by community surveillance. Univariate, bivariate, and multivariate analyses were performed, comparing symptoms and signs according to transmission routes, complications, and age groups. Results: The incidence was 3.16 cases per 100,000 inhabitants, and the fatality rate was 20% in the study period. The most frequent symptoms included: fever 98.1%, myalgia 62.1%, arthralgia 60.2%, and headache 49.5%. There were significant differences in the frequency of myalgia, abdominal pain, and periorbital edema in oral transmission. The main complications were pericardial effusion, myocarditis, and heart failure in the group over 18 years of age. In Casanare, TcI Discrete Typing Unit (DTU) has mainly been identified in humans, triatomines, and reservoirs such as opossums and dogs and TcBat in bats. An increase in the number of acute CD cases was evidenced in March, a period when precipitation increases due to the beginning of the rainy season. Conclusions: The results corroborate the symptomatic heterogeneity of the acute phase of CD, which delays treatment, triggering possible clinical complications. In endemic regions, clinical suspicion, diagnostic capacity, detection, and surveillance programs should be strengthened, including intersectoral public health policies for their prevention and control.
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Affiliation(s)
- Claudia Yaneth Rincón-Acevedo
- Centro de Investigaciones en Microbiología y Biotecnología-UR, Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia.,Maestría en Salud Pública, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia
| | - Andrea Stella Parada-García
- Centro de Investigaciones en Microbiología y Biotecnología-UR, Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia.,Maestría en Salud Pública, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia
| | | | | | | | - Carolina Hernández
- Centro de Investigaciones en Microbiología y Biotecnología-UR, Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Juan David Ramírez
- Centro de Investigaciones en Microbiología y Biotecnología-UR, Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
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23
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McGraw AL, Thomas TM. Military Working Dogs: An Overview of Veterinary Care of These Formidable Assets. Vet Clin North Am Small Anim Pract 2021; 51:933-944. [PMID: 34059265 DOI: 10.1016/j.cvsm.2021.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
For the clinician treating military working dogs, an understanding of how they are sourced, preventive medicine policies, and common disease conditions is paramount in optimizing the delivery of health care. Military personnel rely heavily on the availability of these K-9s, which bring a diverse array of capabilities to myriad operational settings. Anticipating and mitigating common diseases will ensure these dogs continue to serve the needs of US military and allied forces.
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Affiliation(s)
- Andrew L McGraw
- Auburn Veterinary Specialists-Gulf Shores, Auburn University Educational Complex, 21541 Coastal Gateway Boulevard (County Road 8), Gulf Shores, AL 36542, USA.
| | - Todd M Thomas
- Auburn Veterinary Specialists-Gulf Shores, Auburn University Educational Complex, 21541 Coastal Gateway Boulevard (County Road 8), Gulf Shores, AL 36542, USA
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24
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Pino-Marín A, Medina-Rincón GJ, Gallo-Bernal S, Duran-Crane A, Arango Duque ÁI, Rodríguez MJ, Medina-Mur R, Manrique FT, Forero JF, Medina HM. Chagas Cardiomyopathy: From Romaña Sign to Heart Failure and Sudden Cardiac Death. Pathogens 2021; 10:505. [PMID: 33922366 PMCID: PMC8145478 DOI: 10.3390/pathogens10050505] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/10/2021] [Accepted: 04/13/2021] [Indexed: 12/16/2022] Open
Abstract
Despite nearly a century of research and accounting for the highest disease burden of any parasitic disease in the Western Hemisphere, Chagas disease (CD) is still a challenging diagnosis, primarily due to its poor recognition outside of Latin America. Although initially considered endemic to Central and South America, globalization, urbanization, and increased migration have spread the disease worldwide in the last few years, making it a significant public health threat. The international medical community's apparent lack of interest in this disease that was previously thought to be geographically restricted has delayed research on the complex host-parasite relationship that determines myocardial involvement and its differential behavior from other forms of cardiomyopathy, particularly regarding treatment strategies. Multiple cellular and molecular mechanisms that contribute to degenerative, inflammatory, and fibrotic myocardial responses have been identified and warrant further research to expand the therapeutic arsenal and impact the high burden attributed to CD. Altogether, cardiac dysautonomia, microvascular disturbances, parasite-mediated myocardial damage, and chronic immune-mediated injury are responsible for the disease's clinical manifestations, ranging from asymptomatic disease to severe cardiac and gastrointestinal involvement. It is crucial for healthcare workers to better understand CD transmission and disease dynamics, including its behavior on both its acute and chronic phases, to make adequate and evidence-based decisions regarding the disease. This review aims to summarize the most recent information on the epidemiology, pathogenesis, clinical presentation, diagnosis, screening, and treatment of CD, emphasizing on Chagasic cardiomyopathy's (Ch-CMP) clinical presentation and pathobiological mechanisms leading to sudden cardiac death.
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Affiliation(s)
- Antonia Pino-Marín
- School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110131, Colombia; (G.J.M.-R.); (S.G.-B.); (M.J.R.); (J.F.F.); (H.M.M.)
| | - Germán José Medina-Rincón
- School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110131, Colombia; (G.J.M.-R.); (S.G.-B.); (M.J.R.); (J.F.F.); (H.M.M.)
| | - Sebastian Gallo-Bernal
- School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110131, Colombia; (G.J.M.-R.); (S.G.-B.); (M.J.R.); (J.F.F.); (H.M.M.)
- Division of Cardiology, Fundación Cardio-Infantil-Instituto de Cardiología, Bogotá 110131, Colombia; (R.M.-M.); (F.T.M.)
| | - Alejandro Duran-Crane
- Internal Medicine Residency Program, Cleveland Clinic Foundation, Cleveland, OH 44195, USA;
| | - Álvaro Ignacio Arango Duque
- Department of Infectious Diseases, Fundación Cardio-Infantil-Instituto de Cardiología, Bogotá 110131, Colombia;
| | - María Juliana Rodríguez
- School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110131, Colombia; (G.J.M.-R.); (S.G.-B.); (M.J.R.); (J.F.F.); (H.M.M.)
- Division of Cardiology, Fundación Cardio-Infantil-Instituto de Cardiología, Bogotá 110131, Colombia; (R.M.-M.); (F.T.M.)
| | - Ramón Medina-Mur
- Division of Cardiology, Fundación Cardio-Infantil-Instituto de Cardiología, Bogotá 110131, Colombia; (R.M.-M.); (F.T.M.)
| | - Frida T. Manrique
- Division of Cardiology, Fundación Cardio-Infantil-Instituto de Cardiología, Bogotá 110131, Colombia; (R.M.-M.); (F.T.M.)
| | - Julian F. Forero
- School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110131, Colombia; (G.J.M.-R.); (S.G.-B.); (M.J.R.); (J.F.F.); (H.M.M.)
- Division of Radiology, Fundación Cardio-Infantil-Instituto de Cardiología, Bogotá 110131, Colombia
| | - Hector M. Medina
- School of Medicine and Health Sciences, Universidad del Rosario, Bogotá 110131, Colombia; (G.J.M.-R.); (S.G.-B.); (M.J.R.); (J.F.F.); (H.M.M.)
- Division of Cardiology, Fundación Cardio-Infantil-Instituto de Cardiología, Bogotá 110131, Colombia; (R.M.-M.); (F.T.M.)
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25
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da Silva MS. DNA Double-Strand Breaks: A Double-Edged Sword for Trypanosomatids. Front Cell Dev Biol 2021; 9:669041. [PMID: 33937271 PMCID: PMC8085331 DOI: 10.3389/fcell.2021.669041] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 03/29/2021] [Indexed: 01/09/2023] Open
Abstract
For nearly all eukaryotic cells, stochastic DNA double-strand breaks (DSBs) are one of the most deleterious types of DNA lesions. DSB processing and repair can cause sequence deletions, loss of heterozygosity, and chromosome rearrangements resulting in cell death or carcinogenesis. However, trypanosomatids (single-celled eukaryotes parasites) do not seem to follow this premise strictly. Several studies have shown that trypanosomatids depend on DSBs to perform several events of paramount importance during their life cycle. For Trypanosoma brucei, DSBs formation is associated with host immune evasion via antigenic variation. In Trypanosoma cruzi, DSBs play a crucial role in the genetic exchange, a mechanism that is still little explored but appear to be of fundamental importance for generating variability. In Leishmania spp., DSBs are necessary to generate genomic changes by gene copy number variation (CNVs), events that are essential for these organisms to overcome inhospitable conditions. As DSB repair in trypanosomatids is primarily conducted via homologous recombination (HR), most of the events associated with DSBs are HR-dependent. This review will discuss the latest findings on how trypanosomatids balance the benefits and inexorable challenges caused by DSBs.
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Affiliation(s)
- Marcelo Santos da Silva
- DNA Replication and Repair Laboratory (DRRL), Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, Brazil
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26
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Lidani KCF, Sandri TL, Castillo-Neyra R, Andrade FA, Guimarães CM, Marques EN, Beltrame MH, Gilman RH, de Messias-Reason I. Clinical and epidemiological aspects of chronic Chagas disease from Southern Brazil. Rev Soc Bras Med Trop 2020; 53:e20200225. [PMID: 33111908 PMCID: PMC7580281 DOI: 10.1590/0037-8682-0225-2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/31/2020] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION Patients with Chagas disease (CD), caused by Trypanosoma cruzi, present a higher risk of developing other chronic diseases, which may contribute to CD severity. Since CD is underreported in the southern state of Paraná, Brazil, we aimed to characterize clinical and epidemiological aspects of individuals chronically infected with T. cruzi in Southern Brazil. METHODS A community hospital-based study was performed, recording clinical/demographic characteristics of 237 patients with CD from Southern Brazil. To estimate the association between different forms of CD and sociodemographic and clinical variables, multiple logistic regression models were built using the Akaike information criterion. RESULTS Mean age was 57.5 years and 59% were females. Most patients' (60%) place of origin/birth was within Paraná and they were admitted to the CD outpatient clinic after presenting with cardiac/digestive symptoms (64%). The predominant form of CD was cardiac (53%), followed by indeterminate (36%), and digestive (11%). The main electrocardiographic changes were in the right bundle branch block (39%) and left anterior fascicular block (32%). The average number of comorbidities per patient was 3.9±2.3; systemic arterial hypertension was most common (64%), followed by dyslipidemia (34%) and diabetes (19%); overlapping comorbidities were counted separately. Male sex was associated with symptomatic cardiac CD (OR=2.92; 95%CI: 1.05-8.12; p=0.040). CONCLUSIONS This study provided greater understanding of the distribution and clinical profile of CD patients in Southern Brazil, indicating a high prevalence of comorbidities among these patients who are a vulnerable group due to advanced age and substantial risk of morbidity.
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Affiliation(s)
| | - Thaisa Lucas Sandri
- University of Tübingen, Institute of Tropical Medicine, Tübingen,
BW, Germany
| | - Ricardo Castillo-Neyra
- University of Pennsylvania, Perelman School of Medicine, Department
of Biostatistics, Epidemiology & Informatics, Philadelphia, PA, USA
| | - Fabiana Antunes Andrade
- Universidade Federal do Paraná, Departamento de Patologia Médica,
Hospital de Clínicas, Curitiba, PR, Brasil
| | - Cesar Maistro Guimarães
- Universidade Federal do Paraná, Hospital de Clínicas, Unidade de
Terapia Intensiva, Curitiba, PR, Brasil
| | - Eduardo Nunes Marques
- Universidade Federal do Paraná, Departamento de Patologia Médica,
Hospital de Clínicas, Curitiba, PR, Brasil
| | - Marcia Holsbach Beltrame
- Universidade Federal do Paraná, Departamento de Genética,
Laboratório de Genética Molecular Humana, Curitiba, PR, Brasil
| | - Robert Hugh Gilman
- Johns Hopkins Bloomberg School of Public Health, Department of
International Health, Baltimore, MD, USA
| | - Iara de Messias-Reason
- Universidade Federal do Paraná, Departamento de Patologia Médica,
Hospital de Clínicas, Curitiba, PR, Brasil
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27
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Martínez-Peinado N, Cortes-Serra N, Losada-Galvan I, Alonso-Vega C, Urbina JA, Rodríguez A, VandeBerg JL, Pinazo MJ, Gascon J, Alonso-Padilla J. Emerging agents for the treatment of Chagas disease: what is in the preclinical and clinical development pipeline? Expert Opin Investig Drugs 2020; 29:947-959. [PMID: 32635780 DOI: 10.1080/13543784.2020.1793955] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Chagas disease treatment relies on the lengthy administration of benznidazole and/or nifurtimox, which have frequent toxicity associated. The disease, caused by the parasite Trypanosoma cruzi, is mostly diagnosed at its chronic phase when life-threatening symptomatology manifest in approximately 30% of those infected. Considering that both available drugs have variable efficacy by then, and there are over 6 million people infected, there is a pressing need to find safer, more efficacious drugs. AREAS COVERED We provide an updated view of the path to achieve the aforementioned goal. From state-of-the-art in vitro and in vivo assays based on genetically engineered parasites that have allowed high throughput screenings of large chemical collections, to the unfulfilled requirement of having treatment-response biomarkers for the clinical evaluation of drugs. In between, we describe the most promising pre-clinical hits and the landscape of clinical trials with new drugs or new regimens of existing ones. Moreover, the use of monkey models to reduce the pre-clinical to clinical attrition rate is discussed. EXPERT OPINION In addition to the necessary research on new drugs and much awaited biomarkers of treatment efficacy, a key step will be to generalize access to diagnosis and treatment and maximize efforts to impede transmission.
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Affiliation(s)
- Nieves Martínez-Peinado
- Hospital Clínic - University of Barcelona, Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
| | - Nuria Cortes-Serra
- Hospital Clínic - University of Barcelona, Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
| | - Irene Losada-Galvan
- Hospital Clínic - University of Barcelona, Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
| | - Cristina Alonso-Vega
- Hospital Clínic - University of Barcelona, Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
| | - Julio A Urbina
- Venezuelan Institute for Scientific Research , Caracas, Venezuela
| | - Ana Rodríguez
- Department of Microbiology, New York University School of Medicine , New York, NY, USA
| | - John L VandeBerg
- Department of Human Genetics, South Texas Diabetes and Obesity Institute, and Center for Vector-Borne Diseases, The University of Texas Rio Grande Valley , Brownsville/Harlingen/Edinburg, TX, USA
| | - Maria-Jesus Pinazo
- Hospital Clínic - University of Barcelona, Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
| | - Joaquim Gascon
- Hospital Clínic - University of Barcelona, Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
| | - Julio Alonso-Padilla
- Hospital Clínic - University of Barcelona, Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
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28
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Duran-Crane A, Rojas CA, Cooper LT, Medina HM. Cardiac magnetic resonance imaging in Chagas' disease: a parallel with electrophysiologic studies. Int J Cardiovasc Imaging 2020; 36:2209-2219. [PMID: 32613382 DOI: 10.1007/s10554-020-01925-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/25/2020] [Indexed: 10/23/2022]
Abstract
Chagas' disease (CD), caused by the parasite Trypanosoma cruzi, is the leading cause of cardiac disability from infectious diseases in Central and South America. The disease progresses through an extended, asymptomatic form characterized by latency without clinical manifestations into a symptomatic form with cardiac and gastro-intestinal manifestations. In the terminal phase, chronic Chagas' myocarditis results in extensive myocardial fibrosis, chamber enlargement with aneurysms and ventricular tachycardia (VT). Cardiac magnetic resonance imaging (CMR) has proven useful in characterizing myocardial fibrosis (MF). Sub-epicardial and mid-wall fibrosis are less common patterns of MF in CHD than transmural scar, which resembles myocardial infarction. Commonly involved areas of MF include the left ventricular apex and basal infero-lateral wall, suggesting a role for watershed ischemia in the pathophysiology of MF. Electrophysiology studies have helped refine the relationship between MF and VT in this setting. This article reviews the patterns of MF in CHD and correlate these patterns with electrogram patterns to predict risk of ventricular arrhythmias and sudden death.
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Affiliation(s)
- Alejandro Duran-Crane
- Internal Medicine Residency Program, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Carlos A Rojas
- Department of Diagnostic Radiology, Mayo Clinic, Jacksonville, FL, USA
| | - Leslie T Cooper
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Hector M Medina
- Department of Cardiovascular Imaging, Fundación Cardioinfantil, Calle 163a #13B-60, 110131, Bogotá, Colombia.
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29
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Sánchez-Villamil JP, Bautista-Niño PK, Serrano NC, Rincon MY, Garg NJ. Potential Role of Antioxidants as Adjunctive Therapy in Chagas Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9081813. [PMID: 32308809 PMCID: PMC7136780 DOI: 10.1155/2020/9081813] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/02/2020] [Accepted: 03/07/2020] [Indexed: 02/07/2023]
Abstract
Chagas disease (CD) is one of the most important neglected tropical diseases in the American continent. Host-derived nitroxidative stress in response to Trypanosoma cruzi infection can induce tissue damage contributing to the progression of Chagas disease. Antioxidant supplementation has been suggested as adjuvant therapy to current treatment. In this article, we synthesize and discuss the current evidence regarding the use of antioxidants as adjunctive compounds to fight harmful reactive oxygen species and lower the tissue oxidative damage during progression of chronic Chagas disease. Several antioxidants evaluated in recent studies have shown potential benefits for the control of oxidative stress in the host's tissues. Melatonin, resveratrol, the combination of vitamin C/vitamin E (vitC/vitE) or curcumin/benznidazole, and mitochondria-targeted antioxidants seem to be beneficial in reducing plasma and cardiac levels of lipid peroxidation products. Nevertheless, further research is needed to validate beneficial effects of antioxidant therapies in Chagas disease.
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Affiliation(s)
- Juana P. Sánchez-Villamil
- Translational Biomedical Research Group, Centro de Investigaciones, Fundación Cardiovascular de Colombia, Santander, Colombia
- Faculty of Basic Sciences, Universidad Antonio Nariño, Santander, Colombia
| | - Paula K. Bautista-Niño
- Translational Biomedical Research Group, Centro de Investigaciones, Fundación Cardiovascular de Colombia, Santander, Colombia
| | - Norma C. Serrano
- Translational Biomedical Research Group, Centro de Investigaciones, Fundación Cardiovascular de Colombia, Santander, Colombia
| | - Melvin Y. Rincon
- Translational Biomedical Research Group, Centro de Investigaciones, Fundación Cardiovascular de Colombia, Santander, Colombia
| | - Nisha J. Garg
- Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA
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Morais TR, Conserva GAA, Varela MT, Costa-Silva TA, Thevenard F, Ponci V, Fortuna A, Falcão AC, Tempone AG, Fernandes JPS, Lago JHG. Improving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin A. Sci Rep 2020; 10:5467. [PMID: 32214193 PMCID: PMC7096397 DOI: 10.1038/s41598-020-62352-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/20/2020] [Indexed: 01/05/2023] Open
Abstract
Neolignan licarin A (1) was isolated from leaves of Nectandra oppositifolia (Lauraceae) and displayed activity against trypomastigote forms of the etiologic agent of American trypanosomiasis, Trypanosoma cruzi. Aiming for the establishment of SAR, five different compounds (1a - 1e) were prepared and tested against T. cruzi. The 2-allyl derivative of licarin A (1d) exhibited higher activity against trypomastigotes of T. cruzi (IC50 = 5.0 μM and SI = 9.0), while its heterocyclic derivative 1e displayed IC50 of 10.5 μM and reduced toxicity against NCTC cells (SI > 19.0). However, these compounds presented limited oral bioavailability estimation (<85%, Papp <1.0 × 10-6 cm/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (2), vanillyl alcohol (3), isoeugenol (4), and eugenol (5), as well as its corresponding methyl (a), acetyl (b), O-allyl (c), and C-allyl (d) analogues. Vanillin (2) and its acetyl derivative (2b) displayed expressive activity against intracellular amastigotes of T. cruzi with IC50 values of 5.5 and 5.6 μM, respectively, and reduced toxicity against NCTC cells (CC50 > 200 μM). In addition, these simplified analogues showed a better permeability profile (Papp > 1.0 × 10-6 cm/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (3b) and isoeugenol methyl derivative (4a) displayed activity against the extracellular forms of T. cruzi (trypomastigotes) with IC50 values of 5.1 and 8.8 μM respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (1d, 1e, 3d, and 4a) were selected for a mechanism of action study. After a short incubation period (1 h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound 4a, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of T. cruzi and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease.
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Affiliation(s)
- Thiago R Morais
- Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, São Paulo, 09972-270, Brazil
| | - Geanne A Alves Conserva
- Center of Natural Sciences and Humanities, Universidade Federal do ABC, São Paulo, 09210-580, Brazil
| | - Marina T Varela
- Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, São Paulo, 09972-270, Brazil
| | - Thais A Costa-Silva
- Center of Natural Sciences and Humanities, Universidade Federal do ABC, São Paulo, 09210-580, Brazil
| | - Fernanda Thevenard
- Center of Natural Sciences and Humanities, Universidade Federal do ABC, São Paulo, 09210-580, Brazil
| | - Vitor Ponci
- Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, São Paulo, 09972-270, Brazil
| | - Ana Fortuna
- Laboratory of Pharmacology, Faculty of Pharmacy of University of Coimbra, 3000-370, Coimbra, Portugal
- CIBIT/ICNAS - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-370, Coimbra, Portugal
| | - Amílcar C Falcão
- Laboratory of Pharmacology, Faculty of Pharmacy of University of Coimbra, 3000-370, Coimbra, Portugal
- CIBIT/ICNAS - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-370, Coimbra, Portugal
| | - Andre G Tempone
- Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, 01246-000, Brazil
| | - João Paulo S Fernandes
- Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, São Paulo, 09972-270, Brazil.
| | - João Henrique G Lago
- Center of Natural Sciences and Humanities, Universidade Federal do ABC, São Paulo, 09210-580, Brazil.
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Echeverría LE, González CI, Hernandez JCM, Díaz ML, Eduardo Nieto J, López-Romero LA, Rivera JD, Suárez EU, Ochoa SAG, Rojas LZ, Morillo CA. Efficacy of the Benznidazole+Posaconazole combination therapy in parasitemia reduction: An experimental murine model of acute Chagas. Rev Soc Bras Med Trop 2020; 53:e20190477. [PMID: 32049205 PMCID: PMC7083359 DOI: 10.1590/0037-8682-0477-2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/12/2019] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION: Benznidazole (BZL) and Nifurtimox (NFX) are the pharmacological treatment
for acute phase Chagas Disease (CD); however, therapy resistance and
residual mortality development remain important unresolved issues.
Posaconazole (POS) has shown a trypanocidal effect in vivo and in vitro.
Thus, this study aimed at comparing the T. Cruzi parasitic
load-reducing effect of the combination of BZL+POS against that of
monotherapy with either, during acute phase CD, in an experimental murine
model. METHODS Nineteen Wistar rats were randomly allocated to four groups
and inoculated with the trypomastigotes of T. cruzi
strain´s JChVcl1. The rats were administered anti-parasites from day 20-29
post-infection. The Pizzi and Brener method was used for parasitemia
measurement. Longitudinal data analysis for the continuous outcome of
repeated measures was performed using parasitemia as the outcome measured at
days 20, 22, 24, 27, and 29 post-infection. RESULTS All four groups had similar parasitic loads (p=0.143) prior to therapy
initiation. Among the three treatment groups, the BZL+POS (n=5) group showed
the highest mean parasitic load reduction (p=0.000) compared with the
control group. Likewise, the BZL+POS group rats showed an earlier
therapeutic effect and were the only ones without parasites in their
myocardial samples. CONCLUSIONS: Treatment of acute phase CD with BZL+POS was more efficacious at parasitemia
and myocardial injury reduction, compared with monotherapy with either.
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Affiliation(s)
- Luis Eduardo Echeverría
- Grupo de Estudios Epidemiológicos y Salud Pública-FCV, Fundación Cardiovascular de Colombia, Floridablanca, Colombia.,Heart Failure and Heart Transplant Clinic, Fundación Cardiovascular de Colombia, Floridablanca, Colombia
| | - Clara Isabel González
- Basic Sciences Department, Faculty of Medicine. Universidad Industrial de Santander. Grupo de Inmunología y Epidemiología Molecular GIEM, Santander, Bucaramanga, Colombia
| | - Julio Cesar Mantilla Hernandez
- Basic Sciences Department, Faculty of Medicine. Universidad Industrial de Santander. Grupo de Inmunología y Epidemiología Molecular GIEM, Santander, Bucaramanga, Colombia
| | - Martha Lucia Díaz
- Basic Sciences Department, Faculty of Medicine. Universidad Industrial de Santander. Grupo de Inmunología y Epidemiología Molecular GIEM, Santander, Bucaramanga, Colombia
| | - Javier Eduardo Nieto
- Veterinary Department. Universidad Cooperativa de Colombia, Bucaramanga, Santander, Colombia
| | - Luis Alberto López-Romero
- Research Group and Development of Nursing Knowledge (GIDCEN-FCV), Research Institute, Fundación Cardiovascular de Colombia, Floridablanca, Santander, Colombia
| | - Julián David Rivera
- Heart Failure and Heart Transplant Clinic, Fundación Cardiovascular de Colombia, Floridablanca, Colombia
| | - Edwin Uriel Suárez
- Heart Failure and Heart Transplant Clinic, Fundación Cardiovascular de Colombia, Floridablanca, Colombia
| | - Sergio Alejandro Gómez Ochoa
- Grupo de Estudios Epidemiológicos y Salud Pública-FCV, Fundación Cardiovascular de Colombia, Floridablanca, Colombia
| | - Lyda Z Rojas
- Research Group and Development of Nursing Knowledge (GIDCEN-FCV), Research Institute, Fundación Cardiovascular de Colombia, Floridablanca, Santander, Colombia
| | - Carlos A Morillo
- Division of Cardiology, Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Alberta, Canada.,Department of Medicine, Cardiology Division, McMaster University, PHRI-HHSC, Hamilton, Ontario, Canada
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Matthews H, Noulin F. Unexpected encounter of the parasitic kind. World J Stem Cells 2019; 11:904-919. [PMID: 31768219 PMCID: PMC6851008 DOI: 10.4252/wjsc.v11.i11.904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/10/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Both parasitology and stem cell research are important disciplines in their own right. Parasites are a real threat to human health causing a broad spectrum of diseases and significant annual rates morbidity and mortality globally. Stem cell research, on the other hand, focuses on the potential for regenerative medicine for a range of diseases including cancer and regenerative therapies. Though these two topics might appear distant, there are some “unexpected encounters”. In this review, we summarise the various links between parasites and stem cells. First, we discuss how parasites’ own stem cells represent interesting models of regeneration that can be translated to human stem cell regeneration. Second, we explore the interactions between parasites and host stem cells during the course of infection. Third, we investigate from a clinical perspective, how stem cell regeneration can be exploited to help circumvent the damage induced by parasitic infection and its potential to serve as treatment options for parasitic diseases in the future. Finally, we discuss the importance of screening for pathogens during organ transplantation by presenting some clinical cases of parasitic infection following stem cell therapy.
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Affiliation(s)
- Holly Matthews
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
| | - Florian Noulin
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
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Cláudia Freitas Lidani K, Andrade FA, Kozlowski RK, Luz PR, Messias-Reason IJ. Case Report: High Mannose-Binding Lectin Serum Determined by MBL2 Genotype and Risk for Clinical Progression to Chagasic Cardiomyopathy: A Case Report of Three Patients. Am J Trop Med Hyg 2019; 100:93-96. [PMID: 30526728 DOI: 10.4269/ajtmh.17-0701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Chagas disease (CD), caused by infection with the parasite Trypanosoma cruzi, leads to severe cardiomyopathy in 20-30% of patients, whereas the remainder may stay asymptomatic and never develop cardiomyopathy or other clinical manifestations. The underlying cause for this variable outcome is not fully characterized, although previous studies have found high levels of circulating mannose-binding lectin (MBL) to be associated with cardiac failure echocardiographic changes. We report three indeterminate (asymptomatic) chronic Chagas patients who were followed up for 10 years. Two of these patients developed chronic chagasic cardiomyopathy (CCC) during this follow-up period and, when genotyped, were found to be carriers of the high MBL producer HYPA/HYPA genotype, suggesting that genetically determined high MBL serum might be associated with the risk of CCC development. These results suggest the use of MBL quantification and MBL2 genotyping as tools for clinical assessment in patients with chronic CD.
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Affiliation(s)
| | - Fabiana Antunes Andrade
- Laboratory of Molecular Immunopathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil
| | | | - Paola Rosa Luz
- Laboratory of Molecular Immunopathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil
| | - Iara J Messias-Reason
- Laboratory of Molecular Immunopathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil
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Souto EB, Dias-Ferreira J, Craveiro SA, Severino P, Sanchez-Lopez E, Garcia ML, Silva AM, Souto SB, Mahant S. Therapeutic Interventions for Countering Leishmaniasis and Chagas's Disease: From Traditional Sources to Nanotechnological Systems. Pathogens 2019; 8:pathogens8030119. [PMID: 31374930 PMCID: PMC6789685 DOI: 10.3390/pathogens8030119] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 07/29/2019] [Accepted: 07/31/2019] [Indexed: 02/02/2023] Open
Abstract
The incidence of neglected diseases in tropical countries, such as Leishmaniasis and Chagas's disease, is attributed to a set of biological and ecological factors associated with the socioeconomic context of developing countries and with a significant burden to health care systems. Both Leishmaniasis and Chagas's disease are caused by different protozoa and develop diverse symptoms, which depend on the specific species infecting man. Currently available drugs to treat these disorders have limited therapeutic outcomes, frequently due to microorganisms' drug resistance. In recent years, significant efforts have been made towards the development of innovative drug delivery systems aiming to improve bioavailability and pharmacokinetic profiles of classical drug therapy. This paper discusses the key facts of Leishmaniasis and Chagas's disease, the currently available pharmacological therapies and the new drug delivery systems for conventional drugs.
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Affiliation(s)
- Eliana B Souto
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
- CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
| | - João Dias-Ferreira
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
| | - Sara A Craveiro
- Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia, 296, Paranhos, 4200-150 Porto, Portugal
| | - Patrícia Severino
- Laboratory of Nanotechnology and Nanomedicine (LNMED), Institute of Technology and Research (ITP), Av. Murilo Dantas, 300, Aracaju 49010-390, Brazil
- University of Tiradentes (UNIT), Industrial Biotechnology Program, Av. Murilo Dantas 300, Aracaju 49032-490, Brazil
| | - Elena Sanchez-Lopez
- Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
- Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), University of Barcelona, 08028 Barcelona, Spain
| | - Maria L Garcia
- Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
- Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), University of Barcelona, 08028 Barcelona, Spain
| | - Amélia M Silva
- Departamento de Biologia e Ambiente, Universidade de Trás-os-Montes e Alto Douro (UTAD), P.O. Box 1013; 5001-801 Vila Real, Portugal
- Centro de Investigação e de Tecnologias Agro-Ambientais e Biológicas (CITAB-UTAD), 5001-801 Vila Real, Portugal
| | - Selma B Souto
- Department of Endocrinology of Braga Hospital, Sete Fontes, 4710-243 São Victor, Braga, Portugal
| | - Sheefali Mahant
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana 124001, India
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Carvalho TB, Padovani CR, de Oliveira Júnior LR, Latini ACP, Kurokawa CS, Pereira PCM, Dos Santos RM. ACAT-1 gene rs1044925 SNP and its relation with different clinical forms of chronic Chagas disease. Parasitol Res 2019; 118:2343-2351. [PMID: 31236660 DOI: 10.1007/s00436-019-06377-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023]
Abstract
Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), although discovered more than a century ago, is still a not very well-elucidated aspect. Individuals in the chronic phase of the disease may present asymptomatic clinical form or symptomatologies related to the cardiac, digestive systems, or both (mixed clinical form). SNPs (single nucleotide polymorphisms) have been identified as important markers because they constitute about 90% of the variation in the human genome. One of them is localized to the ACAT-1 gene (cholesterol acyltransferase 1) (rs1044925) and has been linked to lipid disorders. Some studies have suggested the interaction between T. cruzi and the lipid metabolism of the host. Therefore, the objective of the present study was to evaluate the association between the ACAT-1 gene rs1044925 SNP in relation to clinical manifestations in patients with chronic Chagas disease. A total of 135 individuals with chronic Chagas disease, 86 (63.7%) asymptomatic individuals and 49 (36.3%) symptomatic patients (22 with cardiac clinical form, 18 with digestive form and 9 with mixed form) participated in the study. To evaluate the polymorphism, the PCR-RFLP technique were used. There was a significant difference and a higher frequency of AA and AC genotypes (p = 0.047 and p = 0.016, respectively) of the ACAT-1 gene in asymptomatic chagasic individuals. The result suggests a protective character of the AA and AC genotypes of the rs1044925 SNP in relation to the presence of symptomatic clinical manifestations of the disease in chronic chagasic individuals.
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Affiliation(s)
- Thaysa Buss Carvalho
- Department of Tropical Diseases, Botucatu Medical School, São Paulo State University (UNESP - Univ Estadual Paulista), Laboratório de Moléstias Infecciosas - UNIPEX - FMB UNESP, Rua Dr. Walter Mauricio Correa s/n, São Paulo, Brazil.
| | - Carlos Roberto Padovani
- Departament of Bioestatistics, Botucatu Biosciences Institute São Paulo State University (UNESP-Univ Estadual Paulista), São Paulo, Brazil
| | - Luiz Roberto de Oliveira Júnior
- Department of Tropical Diseases, Botucatu Medical School, São Paulo State University (UNESP - Univ Estadual Paulista), Laboratório de Moléstias Infecciosas - UNIPEX - FMB UNESP, Rua Dr. Walter Mauricio Correa s/n, São Paulo, Brazil
| | - Ana Carla Pereira Latini
- Department of Tropical Diseases, Botucatu Medical School, São Paulo State University (UNESP - Univ Estadual Paulista), Laboratório de Moléstias Infecciosas - UNIPEX - FMB UNESP, Rua Dr. Walter Mauricio Correa s/n, São Paulo, Brazil.,Departament of Molecular Biology, Lauro de Souza Lima Institute, São Paulo, Brazil
| | - Cilmery Suemi Kurokawa
- Department of Tropical Diseases, Botucatu Medical School, São Paulo State University (UNESP - Univ Estadual Paulista), Laboratório de Moléstias Infecciosas - UNIPEX - FMB UNESP, Rua Dr. Walter Mauricio Correa s/n, São Paulo, Brazil.,Departament of Pediatrics, Botucatu Medical School, São Paulo State University (UNESP-Univ Estadual Paulista), São Paulo, Brazil
| | - Paulo Câmara Marques Pereira
- Department of Tropical Diseases, Botucatu Medical School, São Paulo State University (UNESP - Univ Estadual Paulista), Laboratório de Moléstias Infecciosas - UNIPEX - FMB UNESP, Rua Dr. Walter Mauricio Correa s/n, São Paulo, Brazil
| | - Rodrigo Mattos Dos Santos
- Department of Tropical Diseases, Botucatu Medical School, São Paulo State University (UNESP - Univ Estadual Paulista), Laboratório de Moléstias Infecciosas - UNIPEX - FMB UNESP, Rua Dr. Walter Mauricio Correa s/n, São Paulo, Brazil
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Brown EL, Wilson AS. Using evidence from hair and other soft tissues to infer the need for and receipt of health-related care provision. INTERNATIONAL JOURNAL OF PALEOPATHOLOGY 2019; 25:91-98. [PMID: 30177456 DOI: 10.1016/j.ijpp.2018.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 08/12/2018] [Accepted: 08/20/2018] [Indexed: 06/08/2023]
Abstract
The Bioarchaeology of Care approach developed by Tilley is usually applied to skeletalized human remains, given the usual constraints of preservation bias that are seen with archaeological assemblages. However, other tissues, such as hair are sometimes preserved and can provide a wealth of information that can supplement the skeletal data. Archaeological hair has been analysed for drug compounds for almost thirty years. This article integrates data from hair analyses for coca metabolites, stable light isotope analysis and aDNA to expand the potential of the Bioarchaeology of Care approach using the example of a spontaneously mummified adult female from northern Chile.
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Affiliation(s)
- Emma L Brown
- School of Archaeological and Forensic Sciences, University of Bradford, Richmond Road, Bradford, BD7 1DP, United Kingdom.
| | - Andrew S Wilson
- School of Archaeological and Forensic Sciences, University of Bradford, Richmond Road, Bradford, BD7 1DP, United Kingdom
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37
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Barry MA, Versteeg L, Wang Q, Pollet J, Zhan B, Gusovsky F, Bottazzi ME, Hotez PJ, Jones KM. A therapeutic vaccine prototype induces protective immunity and reduces cardiac fibrosis in a mouse model of chronic Trypanosoma cruzi infection. PLoS Negl Trop Dis 2019; 13:e0007413. [PMID: 31145733 PMCID: PMC6542517 DOI: 10.1371/journal.pntd.0007413] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 04/25/2019] [Indexed: 02/06/2023] Open
Abstract
Chagas disease, caused by the parasite Trypanosoma cruzi, develops into chronic Chagas’ cardiomyopathy in ~30% of infected individuals, characterized by conduction disorders, arrhythmias, heart failure, and even sudden cardiac death. Current anti-parasitic treatments are plagued by significant side effects and poor efficacy in the chronic phase of disease; thus, there is a pressing need for new treatment options. A therapeutic vaccine could bolster the protective TH1-mediated immune response, thereby slowing or halting the progression of chronic Chagas’ cardiomyopathy. Prior work in mice has demonstrated therapeutic efficacy of a Tc24 recombinant protein vaccine in the acute phase of Chagas disease. However, it is anticipated that humans will be vaccinated therapeutically when in the chronic phase of disease. This study investigates the therapeutic efficacy of a vaccine prototype containing recombinant protein Tc24, formulated with an emulsion containing the Toll-like receptor 4 agonist E6020 as an immunomodulatory adjuvant in a mouse model of chronic T. cruzi infection. Among outbred ICR mice vaccinated during chronic T. cruzi infection, there is a significant increase in the number of animals with undetectable systemic parasitemia (60% of vaccinated mice compared to 0% in the sham vaccine control group), and a two-fold reduction in cardiac fibrosis over the control group. The vaccinated mice produce a robust protective TH1-biased immune response to the vaccine, as demonstrated by a significant increase in antigen-specific IFNγ-production, the number of antigen-specific IFNγ-producing cells, and IgG2a antibody titers. Importantly, therapeutic vaccination significantly reduced cardiac fibrosis in chronically infected mice. This is a first study demonstrating therapeutic efficacy of the prototype Tc24 recombinant protein and E6020 stable emulsion vaccine against cardiac fibrosis in a mouse model of chronic T. cruzi infection. Chagas disease is a parasitic infection that can cause severe heart disease. Current treatments do not work well and have significant side effects. Because of this, the authors created a new vaccine prototype with the goal that it could be given to infected people to prevent Chagas-associated heart disease. The vaccine contains a manufactured protein identical to a protein in the parasite (called Tc24) as well as a component to help the body produce a protective immune response (a vaccine adjuvant called E6020). The vaccine would boost the body’s natural immune response to the parasite infection, reducing the number of parasites in the body, and protecting the heart. Frequently, people are not diagnosed until later in the infection, because the early (or acute) stage of disease can be mistaken for a common cold. Because of this, it is important to test the vaccine when given in the later (or chronic) stage of infection. The authors tested the vaccine in a mouse model of chronic T. cruzi infection and found that the vaccinated mice had lower levels of parasites in their body and less damage to their hearts. This research shows promising value of a therapeutic vaccine to prevent Chagas-associated heart disease in a mouse model, with the hope that the same effect could be found in humans one day.
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Affiliation(s)
- Meagan A. Barry
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, United States of America
- Section of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- * E-mail: (MB); (KJ)
| | - Leroy Versteeg
- Section of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Qian Wang
- Section of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Jeroen Pollet
- Section of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Bin Zhan
- Section of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Fabian Gusovsky
- Eisai, Inc., Eisai Inc, Andover, Massachusetts, United States of America
| | - Maria Elena Bottazzi
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Section of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Biology, Baylor University, Waco, Texas, United States of America
| | - Peter J. Hotez
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Section of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Biology, Baylor University, Waco, Texas, United States of America
| | - Kathryn M. Jones
- Section of Tropical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
- * E-mail: (MB); (KJ)
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Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence. Parasitology 2019; 146:914-927. [PMID: 30782223 DOI: 10.1017/s003118201900009x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
AbstractAlthough leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact onTrypanosoma cruziinfection remains poorly understood. By using the framework of a systematic review, we integrated the preclinical and clinical evidence to investigate the relevance of angiotensin-inhibiting drugs onT. cruziinfections. From a comprehensive and structured search in biomedical databases, only original studies were analysed. In preclinical and clinical studies, captopril, enalapril and losartan were RAS-modulating drugs used. The mainin vitrofindings indicated that these drugs increased parasite uptake per host cells, IL-12 expression by infected dendritic cells and IFN-γby T lymphocytes, in addition to attenuating IL-10 and IL-17 production by CD8 + T cells. In animal models, reduced parasitaemia, tissue parasitism, leucocytes infiltration and mortality were often observed inT. cruzi-infected animals receiving RAS-modulating drugs. In patients with Chagas’ disease, these drugs exerted a controversial impact on cytokine and hormone levels, and a limited effect on cardiovascular function. Considering a detailed evaluation of reporting and methodological quality, the current preclinical and clinical evidence is at high risk of bias, and we hope that our critical analysis will be useful in mitigating the risk of bias in further studies.
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The Role of Co-Stimulatory Molecules in Chagas Disease. Cells 2018; 7:cells7110200. [PMID: 30405039 PMCID: PMC6262639 DOI: 10.3390/cells7110200] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 10/29/2018] [Accepted: 11/05/2018] [Indexed: 12/24/2022] Open
Abstract
Chagas disease, caused by Trypanosoma cruzi, is a potentially life-threatening tropical disease endemic to Latin American countries that affects approximately 8 million people. In the chronic phase of the disease, individuals are classified as belonging to the indeterminate clinical form or to the cardiac and/or digestive forms when clinical symptoms are apparent. The relationship between monocytes and lymphocytes may be an important point to help clarify the complexity that surrounds the clinical symptoms of the chronic phase of Chagas disease. The co-stimulatory signals are essential to determining the magnitude of T cell response to the antigen. The signals are known to determine the regulation of subsequent adaptive immune response. However, little is known about the expression and function of these molecules in Chagas disease. Therefore, this review aims to discuss the possible role of main pathways of co-stimulatory molecule-receptor interactions in this pathology that could be crucial to understand the disease dynamics.
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Magarakis M, Macias AE, Tompkins BA, Reis V, Loebe M, Batista R, Salerno TA. Cardiac surgery for Chagas disease. J Card Surg 2018; 33:597-602. [DOI: 10.1111/jocs.13795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Michael Magarakis
- Jackson Memorial Hospital-University of Miami Miller School of Medicine; Department of Surgery, Division of Cardiothoracic Surgery, Cardiac Surgery section; Miami Florida
| | - Alejandro E. Macias
- Department of Surgery; University of Medicine and Health Sciences; Miami Florida
| | - Bryon A. Tompkins
- Department of Surgery; Jackson Memorial Hospital-University of Miami Miller School of Medicine; Miami Florida
| | - Victor Reis
- Jackson Memorial Hospital-University of Miami Miller School of Medicine; Department of Surgery, Division of Cardiothoracic Surgery, Cardiac Surgery section; Miami Florida
| | - Matthias Loebe
- Jackson Memorial Hospital-University of Miami Miller School of Medicine; Department of Surgery, Division of Transplant Surgery; Miami Florida
| | | | - Tomas A. Salerno
- Jackson Memorial Hospital-University of Miami Miller School of Medicine; Department of Surgery, Division of Cardiothoracic Surgery; Miami Florida
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Moreno ÉM, Leal SM, Stashenko EE, García LT. Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide). BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 18:225. [PMID: 30053848 PMCID: PMC6062979 DOI: 10.1186/s12906-018-2293-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 07/18/2018] [Indexed: 11/10/2022]
Abstract
Background Chagas Disease caused by Trypanosoma cruzi infection, is one of the most important neglected tropical diseases (NTD), without an effective therapy for the successful parasite eradication or for the blocking of the disease’s progression, in its advanced stages. Due to their low toxicity, wide pharmacologic spectrum, and potential synergies, medicinal plants as Lippia alba, offer a promising reserve of bioactive molecules. The principal goal of this work is to characterize the inhibitory properties and cellular effects of the Citral and Carvone L. alba chemotype essential oils (EOs) and their main bioactive terpenes (and the synergies among them) on T. cruzi forms. Methods Twelve L. alba EOs, produced under diverse environmental conditions, were extracted by microwave assisted hydrodistillation, and chemically characterized using gas chromatography coupled mass spectrometry. Trypanocidal activity and cytotoxicity were determined for each oil, and their major compounds, on epimastigotes (Epi), trypomastigotes (Tryp), amastigotes (Amas), and Vero cells. Pharmacologic interactions were defined by a matrix of combinations among the most trypanocidal terpenes (limonene, carvone; citral and caryophyllene oxide). The treated cell phenotype was assessed by fluorescent and optic microscopy, flow cytometry, and DNA electrophoresis assays. Results The L. alba EOs displayed significant differences in their chemical composition and trypanocidal performance (p = 0.0001). Citral chemotype oils were more trypanocidal than Carvone EOs, with Inhibitory Concentration 50 (IC50) of 14 ± 1.5 μg/mL, 22 ± 1.4 μg/mL and 74 ± 4.4 μg/mL, on Epi, Tryp and Amas, respectively. Limonene exhibited synergistic interaction with citral, caryophyllene oxide and Benznidazole (decreasing by 17 times its IC50) and was the most effective and selective treatment. The cellular analysis suggested that these oils or their bioactive terpenes (citral, caryophyllene oxide and limonene) could be inducing T. cruzi cell death by an apoptotic-like mechanism. Conclusions EOs extracted from L. alba Citral chemotype demonstrated significant trypanocidal activity on the three forms of T. cruzi studied, and their composition and trypanocidal performance were influenced by production parameters. Citral, caryophyllene oxide, and limonene showed a possible induction of an apoptotic-like phenotype. The best selective anti-T. cruzi activity was achieved by limonene, the effects of which were also synergic with citral, caryophyllene oxide and benznidazole.
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Spina RM, Lozano E, Barrera PA, Agüero MB, Tapia A, Feresin GE, Sosa MÁ. Antiproliferative effect and ultrastructural alterations induced by 5-O-methylembelin on Trypanosoma cruzi. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2018; 46:111-118. [PMID: 30097111 DOI: 10.1016/j.phymed.2018.04.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 02/26/2018] [Accepted: 04/15/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Embelin (EMB), obtained from Oxalis erythrorhiza Gillies ex Hooker et Arnott (Oxalidaceae), was reported against Trypanosoma cruzi and Leishmania spp. Additionally, antiprotozoan activity against Plasmodium falciparum was reported for its methylated derivative (ME). PURPOSE To evaluate the potential anti-Trypanosoma cruzi activity of EMB, ME and 2,5-di-O-methylembelin (DME) and analyze the possible mechanism of action. STUDY DESIGN/METHODS EMB was isolated by a chromatographic method from the air-dried ground whole plant. To evaluate the effects of methylation, ME and DME were synthesized and tested against T. cruzi epimastigotes and trypomastigotes. The most active compound ME was evaluated against amastigotes. Ultrastructural alterations, ROS generation and the effect on mitochondrial activity of ME were measured. RESULTS Compounds inhibited the proliferation of epimastigotes. ME was also active against intracellular amastigotes. Mitochondrial alterations were observed by TEM. Additionally, ME modified the mitochondrial activity, and induced an increase in ROS levels. These evidences postulate the mitochondrion as a possible target of ME. CONCLUSION ME inhibited amastigotes proliferation, thus being a potential lead compound for the treatment of Chagas' disease.
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Affiliation(s)
- Renata María Spina
- Facultad de Ciencias Médicas, Instituto de Histología y Embriología "Dr. Mario H. Burgos", Universidad Nacional de Cuyo-CONICET, CC 56 (5500) Mendoza, Argentina
| | - Esteban Lozano
- Laboratorio de Inmunología y Desarrollo de Vacunas, Instituto de Medicina y Biología Experimental de Cuyo, Av. Ruiz Leal s/n Parque General San Martín, CP 5500 Mendoza, Argentina
| | - Patricia Andrea Barrera
- Facultad de Ciencias Médicas, Instituto de Histología y Embriología "Dr. Mario H. Burgos", Universidad Nacional de Cuyo-CONICET, CC 56 (5500) Mendoza, Argentina
| | - María Belén Agüero
- Instituto de Biotecnología-Instituto de Ciencias Básicas, Universidad Nacional de San Juan, Av. Libertador General San Martín 1109 (O), CP5400 San Juan, Argentina; CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Argentina
| | - Alejandro Tapia
- Instituto de Biotecnología-Instituto de Ciencias Básicas, Universidad Nacional de San Juan, Av. Libertador General San Martín 1109 (O), CP5400 San Juan, Argentina
| | - Gabriela Egly Feresin
- Instituto de Biotecnología-Instituto de Ciencias Básicas, Universidad Nacional de San Juan, Av. Libertador General San Martín 1109 (O), CP5400 San Juan, Argentina; CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Argentina
| | - Miguel Ángel Sosa
- Facultad de Ciencias Médicas, Instituto de Histología y Embriología "Dr. Mario H. Burgos", Universidad Nacional de Cuyo-CONICET, CC 56 (5500) Mendoza, Argentina.
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Abstract
Extracorporeal membrane oxygenation (ECMO) is widely used in acute respiratory distress syndrome (ARDS) and myocarditis. Severe vector-mediated diseases may be complicated by ARDS or myocarditis, which are both associated with a high mortality rate. We present six cases of severe dengue, malaria, and acute Chagas disease that were treated with ECMO from September 2007 to September 2015. Patients included two pediatric and four adults (aged 12-48). Survival to decannulation was 83% and to discharge was 66%. Overall, the mean duration on ECMO was 25.4 days. We conclude that ECMO treatment can be beneficial in patients with severe dengue, malaria, and acute Chagas disease, if complicated by pulmonary or cardiac complications.
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Roscoe A, Tomey MI, Torregrossa G, Galhardo C, Parhar K, Zochios V. Chagas Cardiomyopathy: A Comprehensive Perioperative Review. J Cardiothorac Vasc Anesth 2018; 32:2780-2788. [PMID: 29803311 DOI: 10.1053/j.jvca.2018.04.046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Indexed: 12/28/2022]
Affiliation(s)
- Andrew Roscoe
- Department of Cardiothoracic Anesthesia and Critical Care Medicine, Papworth Hospital, Cambridge, United Kingdom
| | - Matthew I Tomey
- Cardiovascular Institute and Institute for Critical Care Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gianluca Torregrossa
- Department of Cardiothoracic Surgery, Mount Sinai Saint Luke, Mount Sinai Health System, New York, NY
| | - Carlos Galhardo
- Department of Anesthesia, National Institute of Cardiology, Rio de Janeiro, Brazil
| | - Ken Parhar
- Department of Critical Care Medicine, University of Calgary, Calgary, Canada
| | - Vasileios Zochios
- University Hospitals Birmingham NHS Foundation Trust, Department of Critical Care Medicine, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom; Perioperative Critical Care and Trauma Trials Group, Institute of Inflammation and Ageing, Centre of Translational Inflammation Research, University of Birmingham, Birmingham, United Kingdom.
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Nadruz W, Gioli-Pereira L, Bernardez-Pereira S, Marcondes-Braga FG, Fernandes-Silva MM, Silvestre OM, Sposito AC, Ribeiro AL, Bacal F, Fernandes F, Krieger JE, Mansur AJ, Pereira AC. Temporal trends in the contribution of Chagas cardiomyopathy to mortality among patients with heart failure. Heart 2018. [PMID: 29523589 DOI: 10.1136/heartjnl-2017-312869] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Chagas cardiomyopathy (ChC) prevalence is decreasing in Brazil and medical therapies for heart failure (HF) have improved in the last decade. Whether these changes modified the prognosis of ChC relative to non-Chagas cardiomyopathies (NChC) remains unknown. This study evaluated the temporal trends in population attributable risk (PAR) of ChC for 2-year mortality among patients with HF enrolled at years 2002-2004 (era 1) and 2012-2014 (era 2) in a Brazilian university hospital. METHODS We prospectively studied 362 (15% with ChC) and 582 (18% with ChC) HF patients with ejection fraction ≤50% in eras 1 and 2, respectively and estimated the PAR of ChC for 2-year mortality. RESULTS There were 145 deaths (29 in ChC) in era 1 and 85 deaths (26 in ChC) in era 2. In multivariable Cox-regression analysis adjusted for age, sex, ejection fraction, heart rate, body mass index, hypertension, diabetes mellitus, systolic blood pressure and ischaemic/valvar aetiology, ChC was associated with higher risk of death in era 1 (HR (95% CI)=1.92 (1.00 to 3.71), p=0.05) and era 2 (HR (95% CI)=3.51 (1.94 to 6.36), p<0.001). In fully adjusted analysis, the PAR of ChC for mortality increased twofold from era 1 (PAR (95% CI)=11.0 (2.8 to 18.5)%) to era 2 (PAR (95% CI)=21.9 (16.5 to 26.9)%; p=0.023 versus era 1). CONCLUSION Although the absolute death rates decreased over time in the ChC and NChC groups, the PAR of ChC for mortality increased among patients with HF, driven by increases in the HR associated with ChC. Our results highlight the need for additional efforts aiming to prevent and treat ChC.
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Affiliation(s)
- Wilson Nadruz
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
| | | | | | | | - Miguel M Fernandes-Silva
- Medicine Department, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil.,Research Department, Quanta Diagnósticos e Terapia, Curitiba, Brazil
| | - Odilson M Silvestre
- Department of Internal Medicine, Federal University of Acre, Rio Branco, Brazil
| | - Andrei C Sposito
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
| | - Antonio L Ribeiro
- Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Fernando Bacal
- Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Fabio Fernandes
- Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Jose E Krieger
- Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Alfredo J Mansur
- Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Alexandre C Pereira
- Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil
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Hematologic Aspects of Parasitic Diseases. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00158-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023] Open
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Bocchi EA, Bestetti RB, Scanavacca MI, Cunha Neto E, Issa VS. Chronic Chagas Heart Disease Management: From Etiology to Cardiomyopathy Treatment. J Am Coll Cardiol 2017; 70:1510-1524. [PMID: 28911515 DOI: 10.1016/j.jacc.2017.08.004] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 08/01/2017] [Accepted: 08/02/2017] [Indexed: 12/17/2022]
Abstract
Trypanosoma cruzi (T. cruzi) infection is endemic in Latin America and is becoming a worldwide health burden. It may lead to heterogeneous phenotypes. Early diagnosis of T. cruzi infection is crucial. Several biomarkers have been reported in Chagas heart disease (ChHD), but most are nonspecific for T. cruzi infection. Prognosis of ChHD patients is worse compared with other etiologies, with sudden cardiac death as an important mode of death. Most ChHD patients display diffuse myocarditis with fibrosis and hypertrophy. The remodeling process seems to be associated with etiopathogenic mechanisms and neurohormonal activation. Pharmacological treatment and antiarrhythmic therapy for ChHD is mostly based on results for other etiologies. Heart transplantation is an established, valuable therapeutic option in refractory ChHD. Implantable cardioverter-defibrillators are indicated for prevention of secondary sudden cardiac death. Specific etiological treatments should be revisited and reserved for select patients. Understanding and management of ChHD need improvement, including development of randomized trials.
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Affiliation(s)
- Edimar Alcides Bocchi
- Heart Institute (Incor) of São Paulo, University Medical School São Paulo, São Paulo, Brazil.
| | | | | | - Edecio Cunha Neto
- Heart Institute (Incor) of São Paulo, University Medical School São Paulo, São Paulo, Brazil
| | - Victor Sarli Issa
- Heart Institute (Incor) of São Paulo, University Medical School São Paulo, São Paulo, Brazil
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Webber BJ, Pawlak MT, Valtier S, Daniels CC, Tully CC, Wozniak EJ, Roachell WD, Sanchez FX, Blasi AA, Cropper TL. Prevalence and Seroprevalence of Trypanosoma cruzi Infection in a Military Population in Texas. Am J Trop Med Hyg 2017; 97:1477-1481. [PMID: 28820695 PMCID: PMC5817750 DOI: 10.4269/ajtmh.17-0109] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Recent biosurveillance findings at Joint Base San Antonio (JBSA), a large military installation located in south-central Texas, indicate the potential for vector-borne human Chagas disease. A cross-sectional study was conducted to determine the prevalence and seroprevalence of Trypanosoma cruzi infection in highest risk subpopulations on the installation, including students and instructors who work and sleep in triatomine-endemic field settings. Real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and indirect immunofluorescent antibody assay were performed on enrolled subjects (N = 1,033), none of whom tested positive for T. cruzi or anti-T. cruzi antibodies. Current countermeasures used during field training on JBSA appear to be sufficient for preventing autochthonous human Chagas disease.
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Affiliation(s)
- Bryant J Webber
- 59th Medical Wing, Joint Base San Antonio, Lackland, San Antonio, Texas
| | - Mary T Pawlak
- 59th Medical Wing, Joint Base San Antonio, Lackland, San Antonio, Texas
| | - Sandra Valtier
- 59th Medical Wing, Joint Base San Antonio, Lackland, San Antonio, Texas
| | - Candelaria C Daniels
- Brooke Army Medical Center, Joint Base San Antonio, Fort Sam Houston, San Antonio, Texas
| | | | - Edward J Wozniak
- Texas State Guard Medical Brigade Headquarters, Camp Mabry, Austin, Texas
| | - Walter D Roachell
- US Army Public Health Command Central, Joint Base San Antonio, Fort Sam Houston, San Antonio, Texas
| | - Francisco X Sanchez
- US Army Public Health Command Central, Joint Base San Antonio, Fort Sam Houston, San Antonio, Texas
| | - Audra A Blasi
- 59th Medical Wing, Joint Base San Antonio, Lackland, San Antonio, Texas
| | - Thomas L Cropper
- 59th Medical Wing, Joint Base San Antonio, Lackland, San Antonio, Texas
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Durrance RJ, Ullah T, Atif Z, Frumkin W, Doshi K. Chagas Cardiomyopathy Presenting as Symptomatic Bradycardia: An Underappreciated Emerging Public Health Problem in the United States. Case Rep Cardiol 2017; 2017:5728742. [PMID: 28900547 PMCID: PMC5576390 DOI: 10.1155/2017/5728742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 07/18/2017] [Indexed: 11/17/2022] Open
Abstract
Chagas cardiomyopathy (CCM) is traditionally considered a disease restricted to areas of endemicity. However, an estimated 300,000 people living in the United States today have CCM, of which its majority is undiagnosed. We present a case of CCM acquired in an endemic area and detected in its early stage. A 42-year-old El Salvadoran woman presented with recurrent chest pain and syncopal episodes. Significant family history includes a sister in El Salvador who also began suffering similar episodes. Physical exam and ancillary studies were only remarkable for sinus bradycardia. The patient was diagnosed with symptomatic sinus bradycardia and a pacemaker was placed. During her hospital course, Chagas serology was ordered given the epidemiological context from which she came. With no other identifiable cause, CCM was the suspected etiology. This case highlights the underrecognized presence of Chagas in the United States and the economic and public health importance of its consideration in the etiological differential diagnosis of electrocardiographic changes among Latin American immigrants. While the United States is not considered an endemic area for Chagas disease, the influx of Latin American immigrants has created a new challenge to identify at-risk populations, diagnose suspected cases, and provide adequate treatment for this disease.
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Affiliation(s)
- Richard Jesse Durrance
- Department of Internal Medicine, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA
| | - Tofura Ullah
- Department of Internal Medicine, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA
| | - Zulekha Atif
- Department of Internal Medicine, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA
| | - William Frumkin
- Department of Cardiology, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA
| | - Kaushik Doshi
- Department of Internal Medicine, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA
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