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 Resolvin D1 Administration Is Beneficial in Trypanosoma cruzi Infection

2020 ◽  
Vol 88 (6) ◽  
Author(s):  
Aline L. Horta ◽  
Tere Williams ◽  
Bing Han ◽  
Yanfen Ma ◽  
Ana Paula J. Menezes ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Chronic Infection ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Acute Infection ◽  
Public Health Issue ◽  
Resolvin D1 ◽  
Content Type

ABSTRACT Chagas disease is a major public health issue, affecting ∼10 million people worldwide. Transmitted by a protozoan named Trypanosoma cruzi, this infection triggers a chronic inflammatory process that can lead to cardiomyopathy (Chagas disease). Resolvin D1 (RvD1) is a novel proresolution lipid mediator whose effects on inflammatory diseases dampens pathological inflammatory responses and can restore tissue homeostasis. Current therapies are not effective in altering the outcome of T. cruzi infection, and as RvD1 has been evaluated as a therapeutic agent in various inflammatory diseases, we examined if exogenous RvD1 could modulate the pathogenesis of Chagas disease in a murine model. CD-1 mice infected with the T. cruzi Brazil strain were treated with RvD1. Mice were administered 3 μg/kg of body weight RvD1 intraperitoneally on days 5, 10, and 15 to examine the effect of RvD1 on acute disease or administered the same dose on days 60, 65, and 70 to examine its effects on chronic infection. RvD1 therapy increased the survival rate and controlled parasite replication in mice with acute infection and reduced the levels of interferon gamma and transforming growth factor β (TGF-β) in mice with chronic infection. In addition, there was an increase in interleukin-10 levels with RvD1 therapy in both mice with acute infection and mice with chronic infection and a decrease in TGF-β levels and collagen content in cardiac tissue. Together, these data indicate that RvD1 therapy can dampen the inflammatory response, promote the resolution of T. cruzi infection, and prevent cardiac fibrosis.

scholarly journals In VitroandIn VivoStudies of the Antiparasitic Activity of Sterol 14α-Demethylase (CYP51) Inhibitor VNI against Drug-Resistant Strains of Trypanosoma cruzi

2013 ◽  
Vol 57 (9) ◽  
pp. 4151-4163 ◽  
Author(s):  
Maria de Nazaré Correia Soeiro ◽  
Elen Mello de Souza ◽  
Cristiane França da Silva ◽  
Denise da Gama Jaen Batista ◽  
Marcos Meuser Batista ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Acute Infection ◽  
Chronic Phase ◽  
Antifungal Drugs ◽  
Drug Candidate ◽  
Mammalian Host ◽  
Severe Toxicity ◽  
Mutagenic Potential ◽  
Content Type

ABSTRACTChagas disease affects more than 10 million people worldwide, and yet, as it has historically been known as a disease of the poor, it remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years as a result of a lack of interest from pharmaceutical companies. Although attempts to repurpose the antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase [CYP51]) are finally in progress, development of cheaper and more efficient, preferablyTrypanosoma cruzi-specific, chemotherapies would be highly advantageous. We have recently reported that the experimentalT. cruziCYP51 inhibitor VNI cures with 100% survival and 100% parasitological clearance both acute and chronic murine infections with the Tulahuen strain ofT. cruzi. In this work, we further explored the potential of VNI by assaying nitro-derivative-resistantT. cruzistrains, Y and Colombiana, in highly stringent protocols of acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both forms ofT. cruzithat are relevant for mammalian host infection (bloodstream and amastigotes), with thein vivopotency, at 25 mg/kg twice a day (b.i.d.), similar to that of benznidazole (100 mg/kg/day). Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be seen by the Ames test at up to 3.5 μM, and the main ultrastructural damage induced by VNI inT. cruziwas related to Golgi apparatus and endoplasmic reticulum organization, with membrane blebs presenting an autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy.

scholarly journals Mice with Genetic Deletion of Group VIA Phospholipase A2β Exhibit Impaired Macrophage Function and Increased Parasite Load in Trypanosoma cruzi-Induced Myocarditis

2016 ◽  
Vol 84 (4) ◽  
pp. 1137-1142 ◽  
Author(s):  
Janhavi Sharma ◽  
Jennifer R. Blase ◽  
Daniel F. Hoft ◽  
John O. Marentette ◽  
John Turk ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Platelet Activating Factor ◽  
Parasite Load ◽  
Inflammatory Cells ◽  
Myocardial Inflammation ◽  
Wild Type ◽  
Human Coronary Artery ◽  
Content Type

Trypanosoma cruziinfection, which is the etiological agent of Chagas disease, is associated with intense inflammation during the acute and chronic phases. The pathological progression of Chagas disease is influenced by the infiltration and transmigration of inflammatory cells across the endothelium to infected tissues, which are carefully regulated processes involving several molecular mediators, including adhesion molecules and platelet-activating factor (PAF). We have shown that PAF production is dependent upon calcium-independent group VIA phospholipase A2β (iPLA2β) following infection of human coronary artery endothelial cells (HCAECs) withT. cruzi, suggesting that the absence of iPLA2β may decrease the recruitment of inflammatory cells to the heart to manage parasite accumulation. Cardiac endothelial cells isolated from iPLA2β-knockout (iPLA2β-KO) mice infected withT. cruzidemonstrated decreased PAF production compared to that by cells isolated from wild-type (WT) mice but demonstrated increases in adhesion molecule expression similar to those seen in WT mice. Myocardial inflammation in iPLA2β-KO mice infected withT. cruziwas similar in severity to that in WT mice, but the iPLA2β-KO mouse myocardium contained more parasite pseudocysts. Upon activation, macrophages from iPLA2β-KO mice produced significantly less nitric oxide (NO) and caused lessT. cruziinhibition than macrophages from wild-type mice. Thus, the absence of iPLA2β activity does not influence myocardial inflammation, but iPLA2β is essential forT. cruziclearance.

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 Neurotrophin Receptor TrkC Is an Entry Receptor for Trypanosoma cruzi in Neural, Glial, and Epithelial Cells

2011 ◽  
Vol 79 (10) ◽  
pp. 4081-4087 ◽  
Author(s):  
Craig Weinkauf ◽  
Ryan Salvador ◽  
Mercio PereiraPerrin
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Mammalian Cells ◽  
Chinese Hamster ◽  
Neuronal Cell ◽  
Host Cells ◽  
Neurotrophin Receptor ◽  
Content Type

ABSTRACTTrypanosoma cruzi, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated byT. cruzisurfacetrans-sialidase, also known as parasite-derived neurotrophic factor (PDNF). However, it has remained unclear whether TrkC is used byT. cruzito enter host cells. Here, we show that a neuronal cell line (PC12-NNR5) relatively resistant toT. cruzibecame highly susceptible to infection when overexpressing human TrkC but not human TrkB. Furthermore,trkCtransfection conferred an ∼3.0-fold intracellular growth advantage. Sialylation-deficient Chinese hamster ovarian (CHO) epithelial cell lines Lec1 and Lec2 also became much more permissive toT. cruziafter transfection with thetrkCgene. Additionally, NT-3 specifically blockedT. cruziinfection of the TrkC-NNR5 transfectants and of naturally permissive TrkC-bearing Schwann cells and astrocytes, as did recombinant PDNF. Two specific inhibitors of Trk autophosphorylation (K252a and AG879) and inhibitors of Trk-induced MAPK/Erk (U0126) and Akt kinase (LY294002) signaling, but not an inhibitor of insulin-like growth factor 1 receptor, abrogated TrkC-mediated cell invasion. Antibody to TrkC blockedT. cruziinfection of the TrkC-NNR5 transfectants and of cells that naturally express TrkC. The TrkC antibody also significantly and specifically reduced cutaneous infection in a mouse model of acute Chagas' disease. TrkC is ubiquitously expressed in the peripheral and central nervous systems, and in nonneural cells infected byT. cruzi, including cardiac and gastrointestinal muscle cells. Thus, TrkC is implicated as a functional PDNF receptor in cell entry, independently of sialic acid recognition, mediating broadT. cruziinfection bothin vitroandin vivo.

scholarly journals A Parasite Biomarker Set for Evaluating Benznidazole Treatment Efficacy in Patients with Chronic Asymptomatic Trypanosoma cruzi Infection

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Adriana Egui ◽  
M. Carmen Thomas ◽  
Ana Fernández-Villegas ◽  
Elena Pérez-Antón ◽  
Inmaculada Gómez ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Parasite Load ◽  
Drastic Reduction ◽  
Content Type ◽  
Short Period ◽  
Before And After ◽  
Cruzi Infection

ABSTRACT One of the current greatest challenges of Chagas disease is the establishment of biomarkers to assess the efficacy of drugs in a short period of time. In this context, the reactivity of sera from 66 adults with chronic indeterminate Chagas disease (IND) for a set of four Trypanosoma cruzi antigens (KMP11, PFR2, HSP70, and 3973d) was analyzed before and after benznidazole treatment. The results showed that the reactivity against these antigens decreased at 9, 24, and 48 months after treatment. Moreover, the 42.4% and 68.75% of IND patients met the established standard criteria of therapeutic efficacy (STEC) at 24 and 48 months posttreatment, respectively. Meeting the STEC implied that there was a continuous decrease in the reactivity of the patient sera against the four antigens after treatment and that there was a substantial decrease in the reactivity for at least two of the antigens. This important decrease in reactivity may be associated with a drastic reduction in the parasite load, but it is not necessarily associated with a parasitological cure. After treatment, a positive PCR result was only obtained in patients who did not meet the STEC. The percentage of granzyme B+/perforin+ CD8+ T cells was significantly higher in patients who met the STEC than in those who did not meet the STEC (35.2% versus 2.2%; P < 0.05). Furthermore, the patients who met the STEC exhibited an increased quality of the multifunctional response of the antigen-specific CD8+ T cells compared with that in the patients who did not meet the STEC.

scholarly journals Effects of betamethasone on the course of experimentai. Infection with Trypanosoma cruzi

1986 ◽  
Vol 19 (3) ◽  
pp. 161-164 ◽  
Author(s):  
Frederico G.C. Abath ◽  
Yara M. Gomes ◽  
Eridan M. Coutinho ◽  
Silvia M.L. Montenegro ◽  
Maria E.B. Melo ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Acute Phase ◽  
Bacterial Infections ◽  
Acute Infection ◽  
Chronic Phase ◽  
Control Group ◽  
Cumulative Mortality ◽  
Histopathological Findings ◽  
Experimental Group

In this experiment, the effect of betamethasone administered in the early post- acute infection of mice by Trypanosoma cruzi was studied. This drug was administered during 30 days after the 42nd day of infection in a dose of 0.15 mg/day. The betamethasone treatment did not cause fresh outbreaks of parasitemia and the histopathological findings in the chronic phase were not different from those in the control group. The higher cumulative mortality after treatment in the experimental group was due to superimposed bacterial infections. Outbred albino mice infected with low numbers ofY strain Trypanosoma cruzi trypomastigotes were not suitable models for Chagas' disease, since after 7 months of observation only mild histological lesions developed in all the animais. Prolonged betamethasone treatment of mice infected with low numbers o/Trypanosoma cruzi of the Y strain, during the post-acute phase did not aggravate the course of infection.

scholarly journals Characterization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease

2015 ◽  
Vol 59 (8) ◽  
pp. 4669-4679 ◽  
Author(s):  
Nilmar Silvio Moretti ◽  
Leonardo da Silva Augusto ◽  
Tatiana Mordente Clemente ◽  
Raysa Paes Pinto Antunes ◽  
Nobuko Yoshida ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Drug Targets ◽  
Wild Type ◽  
Content Type ◽  
Damage Repair ◽  
Lysine Deacetylases

ABSTRACTAcetylation of lysine is a major posttranslational modification of proteins and is catalyzed by lysine acetyltransferases, while lysine deacetylases remove acetyl groups. Among the deacetylases, the sirtuins are NAD+-dependent enzymes, which modulate gene silencing, DNA damage repair, and several metabolic processes. As sirtuin-specific inhibitors have been proposed as drugs for inhibiting the proliferation of tumor cells, in this study, we investigated the role of these inhibitors in the growth and differentiation ofTrypanosoma cruzi, the agent of Chagas disease. We found that the use of salermide during parasite infection prevented growth and initial multiplication after mammalian cell invasion byT. cruziat concentrations that did not affect host cell viability. In addition,in vivoinfection was partially controlled upon administration of salermide. There are two sirtuins inT. cruzi, TcSir2rp1 and TcSir2rp3. By using specific antibodies and cell lines overexpressing the tagged versions of these enzymes, we found that TcSir2rp1 is localized in the cytosol and TcSir2rp3 in the mitochondrion. TcSir2rp1 overexpression acts to impair parasite growth and differentiation, whereas the wild-type version of TcSir2rp3 and not an enzyme mutated in the active site improves both. The effects observed with TcSir2rp3 were fully reverted by adding salermide, which inhibited TcSir2rp3 expressed inEscherichia coliwith a 50% inhibitory concentration (IC50) ± standard error of 1 ± 0.5 μM. We concluded that sirtuin inhibitors targeting TcSir2rp3 could be used in Chagas disease chemotherapy.

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 Trypanosoma cruzi Phosphomannomutase and Guanosine Diphosphate-Mannose Pyrophosphorylase Ligandability Assessment

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Filip Zmuda ◽  
Sharon M. Shepherd ◽  
Michael A. J. Ferguson ◽  
David W. Gray ◽  
Leah S. Torrie ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Surface ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
De Novo ◽  
Chemical Space ◽  
Nucleotide Sugar ◽  
Content Type ◽  
Life Cycle Stages ◽  
Drug Discovery Program

ABSTRACT Chagas’ disease, which is caused by the Trypanosoma cruzi parasite, has become a global health problem that is currently treated with poorly tolerated drugs that require prolonged dosing. Therefore, there is a clinical need for new therapeutic agents that can mitigate these issues. The phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GDP-MP) enzymes form part of the de novo biosynthetic pathway to the nucleotide sugar GDP-mannose. This nucleotide sugar is used either directly, or indirectly via the formation of dolichol-phosphomannose, for the assembly of all mannose-containing glycoconjugates. In T. cruzi, mannose-containing glycoconjugates include the cell-surface glycoinositol-phospholipids and the glycosylphosphatidylinositol-anchored mucin-like glycoproteins that dominate the cell surface architectures of all life cycle stages. This makes PMM and GDP-MP potentially attractive targets for a drug discovery program against Chagas’ disease. To assess the ligandability of these enzymes in T. cruzi, we have screened 18,117 structurally diverse compounds exploring drug-like chemical space and 16,845 small polar fragment compounds using an assay interrogating the activities of both PMM and GDP-MP enzymes simultaneously. This resulted in 48 small fragment hits, and on retesting 20 were found to be active against the enzymes. Deconvolution revealed that these were all inhibitors of T. cruzi GDP-MP, with compounds 2 and 3 acting as uncompetitive and competitive inhibitors, respectively. Based on these findings, the T. cruzi PMM and GDP-MP enzymes were deemed not ligandable and poorly ligandable, respectively, using small molecules from conventional drug discovery chemical space. This presents a significant hurdle to exploiting these enzymes as therapeutic targets for Chagas’ disease.

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