scholarly journals Assessing the Effectiveness of Curative Benznidazole Treatment in Preventing Chronic Cardiac Pathology in Experimental Models of Chagas Disease

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Amanda Fortes Francisco ◽  
Shiromani Jayawardhana ◽  
Martin C. Taylor ◽  
Michael D. Lewis ◽  
John M. Kelly
Keyword(s):  
Chagas Disease ◽  
Cardiac Fibrosis ◽  
Early Stage ◽  
Population Level ◽  
Heart Tissue ◽  
Experimental Models ◽  
Acute Stage ◽  
Cardiac Pathology ◽  
Content Type ◽  
Chronic Stage

ABSTRACT Chagasic heart disease develops in 30% of those infected with the protozoan parasite Trypanosoma cruzi, but can take decades to become symptomatic. Because of this, it has been difficult to assess the extent to which antiparasitic therapy can prevent the development of pathology. We sought to address this question using experimental murine models, exploiting highly sensitive bioluminescent imaging to monitor curative efficacy. Mice were inoculated with bioluminescent parasites and then cured in either the acute or chronic stage of infection with benznidazole. At the experimental endpoint (5 to 6 months postinfection), heart tissue was removed and assessed for inflammation and fibrosis, two widely used markers of cardiac pathology. Infection of BALB/c and C3H/HeN mice with distinct T. cruzi lineages resulted in greatly increased myocardial collagen content at a group level, indicative of fibrotic pathology. When mice were cured by benznidazole in the acute stage, the development of pathology was completely blocked. However, if treatment was delayed until the chronic stage, cardiac fibrosis was observed in the BALB/c model, although the protective effect was maintained in the case of C3H/HeN mice. These experiments therefore demonstrate that curative benznidazole treatment early in murine T. cruzi infections can prevent the development of cardiac fibrosis. They also show that treatment during the chronic stage can block pathology but the effectiveness varies between infection models. If these findings are extendable to humans, it implies that widespread chemotherapeutic intervention targeted at early-stage infections could play a crucial role in reducing Chagas disease morbidity at a population level.

scholarly journals A systematic review of historical and current trends in Chagas disease

2021 ◽  
Vol 8 ◽  
pp. 204993612110337
Author(s):  
Diego-Abelardo Álvarez-Hernández ◽  
Rodolfo García-Rodríguez-Arana ◽  
Alejandro Ortiz-Hernández ◽  
Mariana Álvarez-Sánchez ◽  
Meng Wu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Chagas Disease ◽  
Case Reports ◽  
Clinical Manifestations ◽  
Human Case ◽  
Acute Stage ◽  
Diagnostic Tools ◽  
Chronic Stage ◽  
Pubmed Database ◽  
Trypanocidal Drugs

Introduction: Chagas disease (CD) is caused by Trypanosoma cruzi. When acquired, the disease develops in stages. For diagnosis, laboratory confirmation is required, and an extensive assessment of the patient’s health should be performed. Treatment consists of the administration of trypanocidal drugs, which may cause severe adverse effects. The objective of our systematic review was to analyze data contained in the CD published case reports to understand the challenges that patients and clinicians face worldwide. Materials and methods: We performed a systematic review following the PRISMA guidance. PubMed database was explored using the terms ‘American trypanosomiasis’ or ‘Chagas disease’. Results were limited to human case reports written in English or Spanish. A total of 258 reports (322 patients) were included in the analysis. Metadata was obtained from each article. Following this, it was analyzed to obtain descriptive measures. Results: From the sample, 56.2% were males and 43.8% were females. Most cases were from endemic countries (85.4%). The most common clinical manifestations were fever during the acute stage (70.0%), dyspnea during the chronic stage in its cardiac form (53.7%), and constipation during the chronic stage in its digestive form (73.7%). Most patients were diagnosed in the chronic stage (72.0%). Treatment was administered in 56.2% of cases. The mortality rate for the acute stage cases was 24.4%, while for the chronic stage this was 28.4%. Discussion: CD is a parasitic disease endemic to Latin America, with increasing importance due to human and vector migration. In this review, we report reasons for delays in diagnosis and treatment, and trends in medical practices. Community awareness must be increased to improve CD’s diagnoses; health professionals should be appropriately trained to detect and treat infected individuals. Furthermore, public health policies are needed to increase the availability of screening and diagnostic tools, trypanocidal drugs, and, eventually, vaccines.

scholarly journals 3D mapping of host-parasite-microbiome interactions reveals metabolic determinants of tissue tropism and disease tolerance in Chagas disease

2019 ◽  
Author(s):  
Ekram Hossain ◽  
Sharmily Khanam ◽  
Chaoyi Wu ◽  
Sharon Lostracco-Johnson ◽  
Diane Thomas ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Large Intestine ◽  
Large Scale ◽  
Scale Effects ◽  
Parasitic Infection ◽  
Parasite Burden ◽  
Acute Stage ◽  
Disease Tolerance ◽  
Chronic Stage ◽  
Spatially Resolved

AbstractChagas disease (CD) is a parasitic infection caused by Trypanosoma cruzi protozoa. Over 8 million people worldwide are T. cruzi-positive, 20-30% of which will develop cardiomyopathy, megaoesophagus and/or megacolon. The mechanisms leading to gastrointestinal (GI) symptom development are however poorly understood. To address this issue, we systematically characterized the spatial impact of experimental T. cruzi infection on the microbiome and metabolome across the GI tract. The largest microbiota perturbations were observed in the proximal large intestine in both acute and chronic disease, with chronic-stage effects also observed in the cecum. Strikingly, metabolomic impact of acute-to-chronic stage transition differed depending on the organ, with persistent large-scale effects of infection primarily in the oesophagus and large intestine, providing a potential mechanism for GI pathology tropism in CD. Infection particularly affected acylcarnitine and lipid metabolism. Building on these observations, treatment of infected mice with carnitine-supplemented drinking water prevented acute-stage mortality with no changes in parasite burden. Overall, these results identified a new mechanism of disease tolerance in CD, with potential for the development of new therapeutic regimens. More broadly, these results highlight the potential of spatially-resolved metabolomic approaches to provide insight into disease pathogenesis, with translational applications for infectious disease drug development.

scholarly journals Limited Ability of Posaconazole To Cure both Acute and Chronic Trypanosoma cruzi Infections Revealed by Highly SensitiveIn VivoImaging

2015 ◽  
Vol 59 (8) ◽  
pp. 4653-4661 ◽  
Author(s):  
Amanda Fortes Francisco ◽  
Michael D. Lewis ◽  
Shiromani Jayawardhana ◽  
Martin C. Taylor ◽  
Eric Chatelain ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Imaging System ◽  
Ex Vivo ◽  
Parasite Burden ◽  
Significant Activity ◽  
Content Type ◽  
Chronic Stage

ABSTRACTThe antifungal drug posaconazole has shown significant activity againstTrypanosoma cruziin vitroand in experimental murine models. Despite this, in a recent clinical trial it displayed limited curative potential. Drug testing is problematic in experimental Chagas disease because of difficulties in demonstrating sterile cure, particularly during the chronic stage of infection when parasite burden is extremely low and tissue distribution is ill defined. To better assess posaconazole efficacy against acute and chronic Chagas disease, we have exploited a highly sensitive bioluminescence imaging system which generates data with greater accuracy than other methods, including PCR-based approaches. Mice inoculated with bioluminescentT. cruziwere assessed byin vivoandex vivoimaging, with cyclophosphamide-induced immunosuppression used to enhance the detection of relapse. Posaconazole was found to be significantly inferior to benznidazole as a treatment for both acute and chronicT. cruziinfections. Whereas 20 days treatment with benznidazole was 100% successful in achieving sterile cure, posaconazole failed in almost all cases. Treatment of chronic infections with posaconazole did however significantly reduce infection-induced splenomegaly, even in the absence of parasitological cure. The imaging-based screening system also revealed that adipose tissue is a major site of recrudescence in mice treated with posaconazole in the acute, but not the chronic stage of infection. Thisin vivoscreening model for Chagas disease is predictive, reproducible and adaptable to diverse treatment schedules. It should provide greater assurance that drugs are not advanced prematurely into clinical trial.

scholarly journals Tolerance of Benznidazole in Treatment of Chagas' Disease in Adults

2010 ◽  
Vol 54 (11) ◽  
pp. 4896-4899 ◽  
Author(s):  
María-Jesús Pinazo ◽  
José Muñoz ◽  
Elizabeth Posada ◽  
Paulo López-Chejade ◽  
Montserrat Gállego ◽  
...  
Keyword(s):  
Public Health ◽  
Side Effects ◽  
Trypanosoma Cruzi ◽  
European Country ◽  
Chagas Disease ◽  
Health Problem ◽  
Public Health Problem ◽  
Acute Stage ◽  
Chronic Stage

ABSTRACT Chagas’ disease is an emerging public health problem in areas where the disease is not endemic. Treatment with benznidazole has shown efficacy in the acute stage of the disease, but its efficacy in the chronic stage remains controversial, and unwanted side effects are more frequent and severe in adults than in children. This study describes the profile of side effects of benznidazole in a cohort of Trypanosoma cruzi-infected patients in a European country.

scholarly journals The Absence of Myocardial Calcium-Independent Phospholipase A2γ Results in Impaired Prostaglandin E2Production and Decreased Survival in Mice with Acute Trypanosoma cruzi Infection

2013 ◽  
Vol 81 (7) ◽  
pp. 2278-2287 ◽  
Author(s):  
Janhavi Sharma ◽  
Christopher S. Eickhoff ◽  
Daniel F. Hoft ◽  
David A. Ford ◽  
Richard W. Gross ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Cardiac Myocytes ◽  
Chagas Disease ◽  
Cardiac Myocyte ◽  
Acute Infection ◽  
Survival Rates ◽  
Platelet Activating Factor ◽  
Acute Stage ◽  
Prostaglandin E ◽  
Content Type

ABSTRACTCardiomyopathy is a serious complication of Chagas' disease, caused by the protozoan parasiteTrypanosoma cruzi. The parasite often infects cardiac myocytes, causing the release of inflammatory mediators, including eicosanoids. A recent study from our laboratory demonstrated that calcium-independent phospholipase A2γ (iPLA2γ) accounts for the majority of PLA2activity in rabbit ventricular myocytes and is responsible for arachidonic acid (AA) and prostaglandin E2(PGE2) release. Thus, we hypothesized that cardiac iPLA2γ contributes to eicosanoid production inT. cruziinfection. Inhibition of the isoform iPLA2γ or iPLA2β, with theRorSenantiomer of bromoenol lactone (BEL), respectively, demonstrated that iPLA2γ is the predominant isoform in immortalized mouse cardiac myocytes (HL-1 cells). Stimulation of HL-1 cells with thrombin, a serine protease associated with microthrombus formation in Chagas' disease and a known activator of iPLA2, increased AA and PGE2release, accompanied by platelet-activating factor (PAF) production. Similarly,T. cruziinfection resulted in increased AA and PGE2release over time that was inhibited by pretreatment with (R)-BEL. Further,T. cruzi-infected iPLA2γ-knockout (KO) mice had lower survival rates and increased tissue parasitism compared to wild-type (WT) mice, suggesting that iPLA2γ-KO mice were more susceptible to infection than WT mice. A significant increase in iPLA2activity was observed in WT mice following infection, whereas iPLA2γ-KO mice showed no alteration in cardiac iPLA2activity and produced less PGE2. In summary, these studies demonstrate thatT. cruziinfection activates cardiac myocyte iPLA2γ, resulting in increased AA and PGE2release, mediators that may be essential for host survival during acute infection. Thus, these studies suggest that iPLA2γ plays a cardioprotective role during the acute stage of Chagas' disease.

scholarly journals Genetic Adjuvantation of a Cell-Based Therapeutic Vaccine for Amelioration of Chagasic Cardiomyopathy

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Vanaja Konduri ◽  
Matthew M. Halpert ◽  
Dan Liang ◽  
Jonathan M. Levitt ◽  
Julio Vladimir Cruz-Chan ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Adenoviral Vector ◽  
Acute Infection ◽  
Cardiac Complications ◽  
Vaccine Platform ◽  
Cardiac Pathology ◽  
Content Type ◽  
Chagasic Cardiomyopathy ◽  
Ifn Γ ◽  
Acute Chagas Disease

ABSTRACT Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is a leading cause of heart disease (“chagasic cardiomyopathy”) in Latin America, disproportionately affecting people in resource-poor areas. The efficacy of currently approved pharmaceutical treatments is limited mainly to acute infection, and there are no effective treatments for the chronic phase of the disease. Preclinical models of Chagas disease have demonstrated that antigen-specific CD8+ gamma interferon (IFN-γ)-positive T-cell responses are essential for reducing parasite burdens, increasing survival, and decreasing cardiac pathology in both the acute and chronic phases of Chagas disease. In the present study, we developed a genetically adjuvanted, dendritic cell-based immunotherapeutic for acute Chagas disease in an attempt to delay or prevent the cardiac complications that eventually result from chronic T. cruzi infection. Dendritic cells transduced with the adjuvant, an adenoviral vector encoding a dominant negative isoform of Src homology region 2 domain-containing tyrosine phosphatase 1 (SHP-1) along with the T. cruzi Tc24 antigen and trans-sialidase antigen 1 (TSA1), induced significant numbers of antigen-specific CD8+ IFN-γ-positive cells following injection into BALB/c mice. A vaccine platform transduced with the adenoviral vector and loaded in tandem with the recombinant protein reduced parasite burdens by 76% to >99% in comparison to a variety of different controls and significantly reduced cardiac pathology in a BALB/c mouse model of live Chagas disease. Although no statistical differences in overall survival rates among cohorts were observed, the data suggest that immunotherapeutic strategies for the treatment of acute Chagas disease are feasible and that this approach may warrant further study.

scholarly journals Lychnopholide in Poly(D,L-Lactide)-Block-Polyethylene Glycol Nanocapsules Cures Infection with a Drug-Resistant Trypanosoma cruzi Strain at Acute and Chronic Phases

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Renata Tupinambá Branquinho ◽  
Carlos Geraldo Campos de Mello ◽  
Maykon Tavares Oliveira ◽  
Levi Eduardo Soares Reis ◽  
Paula Mello de Abreu Vieira ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Chronic Phase ◽  
Heart Tissue ◽  
Oral Route ◽  
Enzyme Linked Immunosorbent Assay ◽  
Drug Resistant ◽  
Content Type ◽  
Negative Results

ABSTRACT Chagas disease remains neglected, and current chemotherapeutics present severe limitations. Lychnopholide (LYC) at low doses loaded in polymeric poly(d,l-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules (LYC-PLA-PEG-NC) exhibits anti-Trypanosoma cruzi efficacy in mice infected with a partially drug-resistant strain. This study reports the efficacy of LYC-PLA-PEG-NC at higher doses in mice infected with a T. cruzi strain resistant to benznidazole (BZ) and nifurtimox (NF) treated at both the acute phase (AP) and the chronic phase (CP) of infection by the oral route. Mice infected with the T. cruzi VL-10 strain were treated by the oral route with free LYC (12 mg/kg of body weight/day), LYC-PLA-PEG-NC (8 or 12 mg/kg/day), or BZ at 100 mg/kg/day or were not treated (controls). Treatment efficacy was assessed by hemoculture (HC), PCR, enzyme-linked immunosorbent assay (ELISA), heart tissue quantitative PCR (qPCR), and histopathology. According to classical cure criteria, treatment with LYC-PLA-PEG-NC at 12 mg/kg/day cured 75% (AP) and 88% (CP) of the animals, while at a dose of 8 mg/kg/day, 43% (AP) and 43% (CP) were cured, showing dose-dependent efficacy. The negative qPCR results for heart tissue and the absence of inflammation/fibrosis agreed with the negative results obtained by HC and PCR. Thus, the mice treated with the highest dose could be considered 100% cured, in spite of a low ELISA reactivity in some animals. No cure was observed in animals treated with free LYC or BZ or the controls. These results are exceptional in terms of experimental Chagas disease chemotherapy and provide evidence of the outstanding contribution of nanotechnology in mice infected with a T. cruzi strain totally resistant to BZ and NF at both phases of infection. Therefore, LYC-PLA-PEG-NC has great potential as a new treatment for Chagas disease and deserves further investigations in clinical trials.

scholarly journals Indexes of Angiogenic Activation in Myocardial Samples of Patients with Advanced Chronic Heart Failure

Medicina ◽  
2019 ◽  
Vol 55 (12) ◽  
pp. 766
Author(s):  
Klara Komici ◽  
Isabella Gnemmi ◽  
Claudia Sangiorgi ◽  
Fabio Luigi Massimo Ricciardolo ◽  
Mauro Rinaldi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Chronic Heart Failure ◽  
Cardiac Fibrosis ◽  
Heart Tissue ◽  
Experimental Models ◽  
Left Ventricular ◽  
Tissue Samples ◽  
Small Series ◽  
Angiopoietin 1

Background and objectives: Ischemic and idiopathic heart failure are characterized by reactive cardiac fibrosis and impaired vasculogenesis involving pro-angiogenic factors such as angiogenin, angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2), as demonstrated in experimental models of heart failure. However, differences in the molecular pathways between these cardiomyopathies are still unclear. In this short communication, we evaluate and compare the expression of pro-angiogenic molecules in the heart tissue of patients with advanced chronic heart failure (CHF) of ischemic vs. nonischemic etiology. Materials and Methods: We obtained heart tissue at transplantation from left ventricular walls of 16 explanted native hearts affected by either ischemic (ICM) or nonischemic dilated cardiomyopathy (NIDCM). Tissue samples were examined using immunohistochemistry for angiogenic molecules. Results: We found immunopositivity (I-pos) for angiopoietin-1 mainly in the cardiomyocytes, while we observed I-pos for Ang-2 and Tie-2 receptor mainly in endothelial cells. Expression of Procollagen-I (PICP), angiogenin, Ang-1, and Tie-2 receptor was similar in ICM and NIDCM. In contrast, endothelial immunopositivity for Ang-2 was higher in ICM samples than NIDCM (p = 0.03). Conclusions: In our series of CHF heart samples, distribution of Ang-1 and angiogenin was higher in cardiomyocytes while that of Ang-2 was higher in endothelial cells; moreover, Ang-2 expression was higher in ICS than NIDCM. Despite the small series examined, these findings suggest different patterns of angiogenic stimulation in ICM and NIDCM, or at least a more altered endothelial integrity in ICD. Our data may contribute to a better understanding of the angiogenesis signaling pathways in CHF. Further studies should investigate differences in the biochemical processes leading to heart failure.

scholarly journals Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection

2015 ◽  
Vol 59 (12) ◽  
pp. 7564-7570 ◽  
Author(s):  
F. H. Guedes-da-Silva ◽  
D. G. J. Batista ◽  
C. F. da Silva ◽  
M. B. Meuser ◽  
M. R. Simões-Silva ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chagas Disease ◽  
Treatment Success ◽  
Experimental Models ◽  
Molecular Diagnostic ◽  
Diagnostic Tools ◽  
Success Rates ◽  
Content Type ◽  
Drug Candidates

ABSTRACTThe lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimentalT. cruziCYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps ofin vivotrials of novel anti-T. cruzidrug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates forin vivoassays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD.

scholarly journals Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas disease

2020 ◽  
Author(s):  
Danya A. Dean ◽  
Gautham ◽  
Jair L. Siqueira-Neto ◽  
James H. McKerrow ◽  
Pieter C. Dorrestein ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Burden ◽  
Heart Tissue ◽  
Blood Transfusions ◽  
Organ Transplants ◽  
Chronic Stage ◽  
Congenital Transmission ◽  
Cardiac Symptoms ◽  
The Impact

AbstractChagas disease (CD) is one of thirteen neglected tropical diseases caused by the parasite Trypanosoma cruzi. CD is a vector-borne disease transmitted by triatomines but CD can also be transmitted through blood transfusions, organ transplants and congenital transmission. While endemic to Latin America, T. cruzi infects 7-8 million people worldwide and can induce severe cardiac symptoms including apical aneurysms, thromboembolisms and arrhythmias during the chronic stage of CD. However, these cardiac clinical manifestations and CD disease pathogenesis are not fully understood. Using spatial metabolomics (chemical cartography), we sought to understand the localized impact of infection on the cardiac metabolome of mice chronically infected with two divergent T. cruzi strains. Our data showed chemical differences in localized cardiac regions upon chronic T. cruzi infection, indicating that parasite infection changes the host metabolome at select sites in chronic CD. These sites were distinct from the sites of highest parasite burden. In addition, we identified acylcarnitines and phosphocholines as discriminatory chemical families within each heart region, comparing infected and uninfected samples. Overall, our study indicated overall and positional metabolic differences common to infection with different T. cruzi strains, and identified select infection-modulated pathways. These results provide further insight into CD pathogenesis and demonstrate the advantage of a spatial perspective to understand infectious disease tropism.Author SummaryChagas disease (CD) is a tropical disease caused by the parasite Trypanosoma cruzi. CD originated in South America; however, there are now 7-8 million people infected worldwide due to population movements. CD is transmitted through a triatomine vector, organ transplants, blood transfusions and congenital transmission. It occurs in two stages, an acute stage (usually asymptomatic) and the chronic stage. Chronic stage CD presents with severe cardiac symptoms such as heart failure, localized aneurysms and cardiomyopathy. Unfortunately, what causes severe cardiac symptoms in some individuals in chronic CD is not fully understood. Therefore, we used liquid chromatography-tandem mass spectrometry to analyze the heart tissue of chronically T. cruzi-infected and uninfected mice, to understand the impact of infection on the tissue metabolome. We identified discriminatory small molecules related to T. cruzi infection. We also determined that regions with the highest parasite burden are distinct from the regions with the largest changes in overall metabolite profile; these locations of high metabolic perturbation provide a molecular mechanism to why localized cardiac symptoms occur in CD. Overall, our work gives insight to chronic cardiac CD symptom development and shapes a framework for novel treatment and biomarker development.

Sign in / Sign up

Export Citation Format

Share Document