Experimental combination therapy using low doses of benznidazole and allopurinol in mouse models of Trypanosoma cruzi chronic infection

Parasitology ◽  
2018 ◽  
Vol 146 (3) ◽  
pp. 305-313 ◽  
Author(s):  
Marcela Silvina Rial ◽  
María Luján Scalise ◽  
Micaela López Alarcón ◽  
Mónica Inés Esteva ◽  
Jacqueline Búa ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chronic Infection ◽  
Chronic Phase ◽  
Preclinical Model ◽  
Low Doses ◽  
Positive Interaction ◽  
Continuous Administration ◽  
Conventional Dose ◽  
Antibody Titres ◽  
Parasitic Effect

AbstractThis study evaluated the effectiveness of low doses of benznidazole (BNZ) on continuous administration (BNZc), combined with allopurinol (ALO), in C57BL/6J and C3H/HeN mice infected with Trypanosoma cruzi Nicaragua strain and T. cruzi Sylvio-X10/4 clone. TcN-C57BL/6J was also treated with intermittent doses of BNZ (BNZit). The drug therapy started 3 months post infection (pi) in the chronic phase of mice with heart disease progression, followed-up at 6 months pi. TcN-C57BL/6J treated with BNZc was also monitored up to 12 months pi by serology and electrocardiogram. These mice showed severe electrical abnormalities, which were not observed after BNZc or BNZit. ALO only showed positive interaction with the lowest dose of BNZ. A clear parasitic effect, with significant reductions in antibody titres and parasitic loads, was achieved in all models with low doses of BNZ, and a 25% reduction of the conventional dose showed more efficacy to inhibit the development of the pathology. However, BNZ 75 showed partial efficacy in the TcSylvio-X10/4-C3H/HeN model. In our experimental designs, C57BL/6J allowed to clearly define a chronic phase, and through reproducible efficacy indicators, it can be considered a good preclinical model.

scholarly journals Hematological changes in mice experimentally infected with Trypanosoma Cruzi

1980 ◽  
Vol 75 (3-4) ◽  
pp. 97-104 ◽  
Author(s):  
Jarbas E. Cardoso ◽  
Z. Brener
Keyword(s):  
Trypanosoma Cruzi ◽  
Chronic Infection ◽  
Normal Values ◽  
Acute Infection ◽  
Chronic Phase ◽  
Precursor Cells ◽  
Direct Damage ◽  
Hematological Changes

Mice inoculated with trypanosoma cruzi display an intense thrombocytopenia which is more severe in animals infected with the Y than CL strain. In animals inoculated with a T. cruzi strain which induces chronic infection (Colombiana), the number of platelets decreases as parasitemia ascends, and then reverts to normal values as soon as the acute infection merges into the chronic phase. The mechanisms involved in the thrombocytopenia are still obscure and are likely to be related to more general phenomena affecting the host rather than to direct damage of platelets or precursor cells by parasitism. Anemia and leukopenia are also present in T. cruzi infected mice.

Assessing the effectiveness of AS-48 in experimental mice models of Chagas’ disease

2020 ◽  
Vol 75 (6) ◽  
pp. 1537-1545 ◽  
Author(s):  
Rubén Martín-Escolano ◽  
Rubén Cebrián ◽  
Mercedes Maqueda ◽  
Desirée Romero ◽  
Maria José Rosales ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Enterococcus Faecalis ◽  
Chagas Disease ◽  
Chronic Infection ◽  
Acute Infection ◽  
Chronic Phase ◽  
Aetiological Agent ◽  
Promising Alternative ◽  
Parasitic Load

Abstract Objectives We report the in vivo trypanocidal activity of the bacteriocin AS-48 (lacking toxicity), which is produced by Enterococcus faecalis, against the flagellated protozoan Trypanosoma cruzi, the aetiological agent of Chagas’ disease. Methods We determined the in vivo activity of AS-48 against the T. cruzi Arequipa strain in BALB/c mice (in both acute and chronic phases of Chagas’ disease). We evaluated the parasitaemia, the reactivation of parasitaemia after immunosuppression and the nested parasites in the chronic phase by PCR in target tissues. Results AS-48 reduced the parasitaemia profile in acute infection and showed a noteworthy reduction in the parasitic load in chronic infection after immunosuppression according to the results obtained by PCR (double-checking to demonstrate cure). Conclusions AS-48 is a promising alternative that provides a step forward in the development of a new therapy against Chagas’ disease.

Dynamics of T Cells Repertoire During Trypanosoma cruzi Infection and its Post-Treatment Modulation

2019 ◽  
Vol 26 (36) ◽  
pp. 6519-6543 ◽  
Author(s):  
Adriana Egui ◽  
Paola Lasso ◽  
Elena Pérez-Antón ◽  
M. Carmen Thomas ◽  
Manuel Carlos López
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Cardiac Tissue ◽  
Acute Infection ◽  
Clinical Status ◽  
Chronic Phase ◽  
Parasite Load ◽  
Chronic Patients ◽  
Cruzi Infection

Chagas disease courses with different clinical phases and has a variable clinical presentation and progression. The acute infection phase mostly exhibits a non-specific symptomatology. In the absence of treatment, the acute phase is followed by a chronic phase, which is initially asymptomatic. This chronic asymptomatic phase of the disease is characterized by a fragile balance between the host’s immune response and the parasite replication. The loss of this balance is crucial for the progression of the sickness. The virulence and tropism of the T. cruzi infecting strain together to the inflammation processes in the cardiac tissue are the main factors for the establishment and severity of the cardiomyopathy. The efficacy of treatment in chronic Chagas disease patients is controversial. However, several studies carried out in chronic patients demonstrated that antiparasitic treatment reduces parasite load in the bloodstream and leads to an improvement in the immune response against the Trypanosoma cruzi parasite. The present review is mainly focused on the cellular patterns associated to the clinical status and the evolution of the disease in chronic patients, as well as the effectiveness of the treatment related to T. cruzi infection control. Therefore, an emphasis is placed on the dynamics of specific-antigens T cell subpopulations, their memory and activation phenotypes, their functionality and their contribution to pathogenesis or disease control, as well as their association with risk of congenital transmission of the parasite.

scholarly journals Quintuple Deglycosylation Mutant of Simian Immunodeficiency Virus SIVmac239 in Rhesus Macaques: Robust Primary Replication, Tightly Contained Chronic Infection, and Elicitation of Potent Immunity against the Parental Wild-Type Strain

2001 ◽  
Vol 75 (9) ◽  
pp. 4023-4028 ◽  
Author(s):  
Kazuyasu Mori ◽  
Yasuhiro Yasutomi ◽  
Shinji Ohgimoto ◽  
Tadashi Nakasone ◽  
Shiki Takamura ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Chronic Infection ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Chronic Phase ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Challenge Virus ◽  
Culture Cells ◽  
Immunodeficiency Virus

ABSTRACT We previously generated a mutant of simian immunodeficiency virus (SIV) lacking 5 of a total of 22 N-glycans in its external envelope protein gp120 with no impairment in viral replication capability and infectivity in tissue culture cells. Here, we infected rhesus macaques with this mutant and found that it also replicated robustly in the acute phase but was tightly, though not completely, contained in the chronic phase. Thus, a critical requirement for the N-glycans for the full extent of chronic infection was demonstrated. No evidence indicating reversion to a wild type was obtained during the observation period of more than 40 weeks. Monkeys infected with the mutant were found to tolerate a challenge infection with wild-type SIV very well. Analyses of host responses following challenge revealed no neutralizing antibodies against the challenge virus but strong secondary responses of cytotoxic T lymphocytes against multiple antigens, including Gag-Pol, Nef, and Env. Thus, the quintuple deglycosylation mutant appeared to represent a novel class of SIV live attenuated vaccine.

Abstract 83: Modulation of Macrophage Function via Metabolism by Trypanosoma cruzi

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sue-Jie Koo ◽  
Nisha J Garg
Keyword(s):  
Trypanosoma Cruzi ◽  
Chronic Phase ◽  
Etiologic Agent ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Transcription Control ◽  
Metabolic Gene Expression ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors ◽  
The Impact

Chagas heart disease is an inflammatory cardiomyopathy which presents with mononuclear infiltrates in the interstitium and myocardial fibrosis in the chronic phase. Incomplete clearance by macrophages of the etiologic agent, Trypanosoma cruzi , is a significant cause of chronic disease development in approximately 30% of those serologically positive for the blood-borne parasite. The differential metabolic status, anaerobic glycolysis and mitochondria-dependent oxidative phosphorylation, are respectively associated with pro-inflammatory (M1) and anti-inflammatory (M2) functional activation of macrophages. Reactive oxygen species (ROS) have been shown to be an intracellular signal for glycolysis while peroxisome proliferator-activated receptors (PPARs) that enhance fatty acid oxidation provide transcription control of macrophage functional state. In our studies using diverse T. cruzi isolates, we showed that SylvioX10 (virulent), but not TCC (non-virulent), isolates are able to differentially control extracellular and intracellular ROS levels in macrophages. We found in macrophages infected with SylvioX10, the nuclear expression of PPAR-α was increased by 18 hours post-infection, and mitochondrial metabolic activity was similar to that of not-infected and M2 controls; which indicates anti-inflammatory function of macrophages, and therefore prohibiting T. cruzi clearance. In our ongoing studies, we are examining the impact of PPAR-α inhibitors in modulating the metabolic gene expression profile, functional phenotype and parasite survival in macrophages. Our data will provide the first indication that host macrophages have deficient pro-inflammatory capacity due to sub-optimal glucose oxidation, and enhancing the metabolism that supports T. cruzi clearance will provide a valuable basis for a strategy to arrest Chagas disease progression.

scholarly journals Immunoblotting analyses using two-dimensional gel electrophoresis of Trypanosoma cruzi excreted-secreted antigens

2004 ◽  
Vol 37 (6) ◽  
pp. 454-459
Author(s):  
Adriano Gomes Silva ◽  
Elisangela Paula Silveira-Lacerda ◽  
Jair Pereira Cunha-Júnior ◽  
Maria Aparecida de Souza ◽  
Silvio Favoreto Junior
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Gel Electrophoresis ◽  
Complex Mixture ◽  
Chronic Phase ◽  
Disease Diagnosis ◽  
Basic Knowledge ◽  
Two Dimensional ◽  
Two Dimensional Gel Electrophoresis ◽  
Secreted Antigens

Trypanosoma cruzi trypomastigotes excrete-secrete a complex mixture of antigenic molecules. This antigenic mixture denominated trypomastigote excreted-secreted antigens contains a 150-160 kDa band that shows excellent performance in Chagas' disease diagnosis by immunoblotting. The present study partially characterized by two-dimensional gel electrophoresis the immunoreactivity against the 150-160kDa protein using sera samples from chagasic patients in different phases of the disease. Trypomastigote excreted-secreted antigen preparations were subjected to high-resolution two-dimensional (2D) gel electrophoresis followed by immunoblotting with sera from chagasic and non-chagasic patients. The 150-160kDa protein presented four isoforms with isoelectric focusing ranging from 6.2 to 6.7. The four isoforms were recognized by IgM from acute phase and IgG from chronic phase sera of chagasic patients. The 150-160kDa isoform with IF of approximately 6.4 became the immunodominant spot with the progression of the disease. No cross-reactivity was observed with non-chagasic or patients infected with Leishmania sp. In this study we provide basic knowledge that supports the validation of trypomastigote excreted-secreted antigens for serological diagnosis of Chagas' disease.

scholarly journals High seroconversion rates in Trypanosoma cruzi chronic infection treated with benznidazole in people under 16 years in Guatemala

2016 ◽  
Vol 49 (6) ◽  
pp. 721-727 ◽  
Author(s):  
Lucia Brum-Soares ◽  
Juan-Carlos Cubides ◽  
Iris Burgos ◽  
Carlota Monroy ◽  
Leticia Castillo ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chronic Infection

scholarly journals Investigation on the possibility of spontaneous cure of mice infected with different strains of Trypanosoma cruzi

1994 ◽  
Vol 36 (6) ◽  
pp. 481-484 ◽  
Author(s):  
Juracy B. Magalhães ◽  
Sonia G. Andrade
Keyword(s):  
Body Weight ◽  
Trypanosoma Cruzi ◽  
Chronic Infection ◽  
Initial Phase ◽  
Newborn Mice ◽  
Blood Examination ◽  
Spontaneous Cure ◽  
Single Exception ◽  
Duration Of Infection ◽  
Different Strains

Seventy Swiss mice chronically infected with different strains of Trypanosoma cruzi, with persistently negative parasitemia on routine blood examination were parasitologically investigated to find out whether spontaneous cure occurred. Duration of infection varied from 90 to 250 days in the initial phase of this investigation. Parasitological tests consisted of daily direct blood examination performed during at least 25 days, followed by xenodiagnosis and subinoculation of blood into newborn mice. Mice that persisted negative were treated with Cyclophosphamide with one dose of 250 mg/kg of body weight and then investigated by direct blood examination, xenodiagnosis and subinoculation. A second dose of 250 mg/kg b. w. was given to the persistently negative mice. With one single exception, all mice showed positive parasitological tests in the different stages of the present investigation and we conclude that spontaneous cure did not occur in this group, which is representative of the chronic infection with different strains of T cruzi.

scholarly journals Neuronal changes caused by Trypanosoma cruzi: an experimental model

2011 ◽  
Vol 83 (2) ◽  
pp. 545-555 ◽  
Author(s):  
Neide M Moreira ◽  
Débora M. G Sant'ana ◽  
Eduardo J. A Araújo ◽  
Max J. O Toledo ◽  
Mônica L Gomes ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Experimental Model ◽  
Morphometric Analysis ◽  
Chronic Phase ◽  
Post Inoculation ◽  
Male Mice ◽  
Neuronal Density ◽  
Myenteric Neurons ◽  
Time Of Infection ◽  
Neuronal Hypertrophy

Define an experimental model by evaluating quantitative and morphometric changes in myenteric neurons of the colon of mice infected with Trypanosoma cruzi. Twenty-eight Swiss male mice were distributed into groups: control (CG, n=9) and inoculated with 100 (IG100, n=9) and 1000 (IG1000, n=10) blood trypomastigotes, Y strain-T. cruzi II. Parasitemia was evaluated from 3-25 days post inoculation (dpi) with parasites peak of 7.7 × 10(6) and 8.4 × 10(6) trypomastigotes/mL at 8th dpi (p>0.05) in IG100 and IG1000, respectively. Chronic phase of the infection was obtained with two doses of 100mg/Kg/weight and one dose of 250mg/Kg/weight of Benznidazole on 11, 16 and 18 dpi. Three animals from each group were euthanized at 18, 30 and 75 dpi. The colon was stained with Giemsa. The quantitative and morphometric analysis of neurons revealed that the infection caused a decrease of neuronal density on 30th dpi (p<0.05) and 75 dpi (p<0.05) in IG100 and IG1000. Infection caused death and neuronal hypertrophy in the 75th dpi in IG100 and IG1000 (p<0.05, p<0.01). The changes observed in myenteric neurons were directly related to the inoculate and the time of infection

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