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1.
PLoS Negl Trop Dis ; 14(12): e0008932, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33332357

RESUMO

BACKGROUND: Chagas disease is a neglected zoonosis of growing concern in the southern US, caused by the parasite Trypanosoma cruzi. We genotyped parasites in a large cohort of PCR positive dogs to shed light on parasite transmission cycles and assess potential relationships between parasite diversity and serological test performance. METHODOLOGY/PRINCIPAL FINDINGS: We used a metabarcoding approach based on deep sequencing of T. cruzi mini-exon marker to assess parasite diversity. Phylogenetic analysis of 178 sequences from 40 dogs confirmed the presence of T. cruzi discrete typing unit (DTU) TcI and TcIV, as well as TcII, TcV and TcVI for the first time in US dogs. Infections with multiple DTUs occurred in 38% of the dogs. These data indicate a greater genetic diversity of T. cruzi than previously detected in the US. Comparison of T. cruzi sequence diversity indicated that highly similar T. cruzi strains from these DTUs circulate in hosts and vectors in Louisiana, indicating that they are involved in a shared T. cruzi parasite transmission cycle. However, TcIV and TcV were sampled more frequently in vectors, while TcII and TcVI were sampled more frequently in dogs. CONCLUSIONS/SIGNIFICANCE: These observations point to ecological host-fitting being a dominant mechanism involved in the diversification of T. cruzi-host associations. Dogs with negative, discordant or confirmed positive T. cruzi serology harbored TcI parasites with different mini-exon sequences, which strongly supports the hypothesis that parasite genetic diversity is a key factor affecting serological test performance. Thus, the identification of conserved parasite antigens should be a high priority for the improvement of current serological tests.


Assuntos
Doença de Chagas/veterinária , Éxons/genética , Variação Genética , Trypanosoma cruzi/genética , Animais , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Doença de Chagas/transmissão , Estudos de Coortes , Cães , Genótipo , Humanos , Louisiana/epidemiologia , Filogenia , Testes Sorológicos/veterinária , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/fisiologia , Zoonoses
2.
PLoS Negl Trop Dis ; 14(9): e0008712, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970687

RESUMO

BACKGROUND: Several studies addressed changes on the insect vector behavior due to parasite infection, but little is known for triatomine bugs, vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. We assessed infection rates and metacyclogenesis of T. cruzi (TcVI) in fifth-instar nymphs of Triatoma rubrovaria comparing with the primary vector Triatoma infestans. Also, biological parameters related to feeding-excretion behavior were evaluated aiming to identify which variables are most influenced by T. cruzi infection. METHODOLOGY/PRINCIPAL FINDINGS: Fifth-instar nymphs of T. rubrovaria and T. infestans were fed on mice infected with T. cruzi (TcVI). We compared the presence and the number of parasite evolutive forms in excreta of both triatomine species at 30, 60 and 90 days post-infection (dpi) with traditional statistical analyses. Moreover, both species were analyzed through generalized linear models and multinomial logistic regression hypotheses for seven behavioral parameters related to host-seeking and feeding-excretion. Triatoma rubrovaria and T. infestans had similar overall infection and metacyclogenesis rates of T. cruzi TcVI in laboratory conditions. Regarding vector behavior, we confirmed that the triatomine's tendency is to move away from the bite region after a blood meal, probably to avoid being noticed by the vertebrate host. Interspecific differences were observed on the volume of blood ingested and on the proportion of individuals that excreted after the blood meal, revealing the higher feeding efficiency and dejection rates of T. infestans. The amount of ingested blood and the bite behavior of T. rubrovaria seems to be influenced by TcVI infection. Infected specimens tended to ingest ~25% more blood and to bite more the head of the host. Noteworthy, in two occasions, kleptohematophagy and coprophagy behaviors were also observed in T. rubrovaria. CONCLUSIONS/SIGNIFICANCE: Laboratory infections revealed similar rate of T. cruzi TcVI trypomatigotes in excreta of T. rubrovaria and T. infestans, one of the most epidemiological important vectors of T. cruzi. Therefore, TcVI DTU was able to complete its life cycle in T. rubrovaria under laboratory conditions, and this infection changed the feeding behavior of T. rubrovaria. Considering these results, T. rubrovaria must be kept under constant entomological surveillance in Rio Grande do Sul, Brazil.


Assuntos
Comportamento Alimentar , Insetos Vetores/fisiologia , Insetos Vetores/parasitologia , Triatoma/fisiologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Brasil , Doença de Chagas/transmissão , Modelos Animais de Doenças , Interações Hospedeiro-Parasita , Mordeduras e Picadas de Insetos , Modelos Logísticos , Camundongos , Ninfa , Eliminação Renal , Trypanosoma cruzi/patogenicidade
3.
PLoS Negl Trop Dis ; 14(8): e0008402, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797041

RESUMO

A Trypanosoma cruzi Loopamp kit was recently developed as a ready-to-use diagnostic method requiring minimal laboratory facilities. We evaluated its diagnostic accuracy for detection of acute Chagas disease (CD) in different epidemiological and clinical scenarios. In this retrospective study, a convenience series of clinical samples (venous blood treated with EDTA or different stabilizer agents, heel-prick blood in filter paper or cerebrospinal fluid samples (CSF)) from 30 infants born to seropositive mothers (13 with congenital CD and 17 noninfected), four recipients of organs from CD donors, six orally-infected cases after consumption of contaminated guava juice and six CD patients coinfected with HIV at risk of CD reactivation (N = 46 patients, 46 blood samples and 1 CSF sample) were tested by T. cruzi Loopamp kit (Tc LAMP) and standardized quantitative real-time PCR (qPCR). T. cruzi Loopamp accuracy was estimated using the case definition in the different groups as a reference. Cohen's kappa coefficient (κ) was applied to measure the agreement between Tc LAMP (index test) and qPCR (reference test). Sensitivity and specificity of T. cruzi Loopamp kit in blood samples from the pooled clinical groups was 93% (95% CI: 77-99) and 100% (95% CI: 80-100) respectively. The agreement between Tc LAMP and qPCR was almost perfect (κ = 0.92, 95% CI: 0.62-1.00). The T. cruzi Loopamp kit was sensitive and specific for detection of T. cruzi infection. It was carried out from DNA extracted from peripheral blood samples (via frozen EDTA blood, guanidine hydrochloride-EDTA blood, DNAgard blood and dried blood spots), as well as in CSF specimens infected with TcI or TcII/V/VI parasite populations. The T. cruzi Loopamp kit appears potentially useful for rapid detection of T. cruzi infection in congenital, acute and CD reactivation due to HIV infection.


Assuntos
Doença de Chagas/sangue , Doença de Chagas/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , Trypanosoma cruzi/isolamento & purificação , Doença de Chagas/líquido cefalorraquidiano , Doença de Chagas/congênito , Coinfecção , DNA de Protozoário/análise , Feminino , Infecções por HIV , Humanos , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estudos Retrospectivos , Sensibilidade e Especificidade , Transplantados , Trypanosoma cruzi/fisiologia
4.
Life Sci ; 258: 118137, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712299

RESUMO

AIMS: Chagas disease is a neglected tropical disease. The ability of Trypanosoma cruzi to survive within phagocytes is likely a critical factor for T. cruzi dissemination in the host. For control of the parasite load and host survival, macrophage action is required. Concanavalin-A (Con-A) presents properties that modulate immune functions and protect hosts from several experimental infectious diseases. Here, we evaluated the effects of Con-A on peritoneal macrophages as well as on the course of experimental infection by T. cruzi. MAIN METHODS: BALB/c mice, a susceptible model for T. cruzi infection, were treated with Con-A via the intraperitoneal route and 3 days later infected with T. cruzi. We quantified parasitemia, cytokines and nitric oxide (NO). Peritoneal exudate and macrophages were collected for macrophage phenotyping and cell viability, NO and cytokine detection, as well as for T. cruzi internalization and release index determination. KEY FINDINGS: Con-A treatment induced IL-17a and NO production by cells from the peritoneal cavity, and M1 marker expression predominated on peritoneal macrophages. These cells are also more prone to producing TNF-α, IL-6 and NO when infected by T. cruzi and show high trypanocidal capacity. Due to a hostile peritoneal microenvironment caused by Con-A, which induces macrophage cNOS and iNOS expression, infected BALB/c mice showed reduced parasitemia and an increased survival rate. SIGNIFICANCE: We conclude that Con-A can induce peritoneal M1 macrophage polarization to increase trypanocidal activity, resulting in ameliorated systemic infection in a susceptible experimental model.


Assuntos
Polaridade Celular , Doença de Chagas/patologia , Concanavalina A/farmacologia , Interleucina-17/metabolismo , Macrófagos Peritoneais/patologia , Macrófagos Peritoneais/parasitologia , Óxido Nítrico/metabolismo , Trypanosoma cruzi/fisiologia , Animais , Polaridade Celular/efeitos dos fármacos , Doença de Chagas/metabolismo , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Parasitemia/metabolismo , Parasitemia/patologia , Trypanosoma cruzi/efeitos dos fármacos
5.
Am J Trop Med Hyg ; 103(3): 967-969, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32602437

RESUMO

In the United States, Chagas disease is diagnosed in less than 1% of the estimated > 300,000 people who have the disease. However, the actual prevalence remains unknown, and these estimates may be wide of the mark (too high or too low). The greater part of those living with the disease acquired the infection in an endemic region of Latin America, but autochthonous transmission in the United States is increasingly being described. These cases are considered rare, and the transmission routes are largely unknown. Although triatomines or "kissing bugs" harbor Trypanosoma cruzi in North America, most autochthonous cases are presumed rather than confirmed exposures to naturally infected kissing bugs. Public knowledge of Chagas is growing, and efforts are underway to provide greater awareness, but what are the risk factors for human transmission of Chagas disease in the United States?


Assuntos
Doença de Chagas/epidemiologia , Doença de Chagas/transmissão , Insetos Vetores/parasitologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/parasitologia , Transmissão de Doença Infecciosa , Humanos , América Latina/epidemiologia , Prevalência , Trypanosoma cruzi/patogenicidade , Incerteza , Estados Unidos/epidemiologia
6.
Parasitol Res ; 119(10): 3517-3522, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32617725

RESUMO

The parasite-vector interaction of Chagas disease is still poorly understood and the understanding of this relationship can help in the development of new strategies to control Trypanosoma cruzi transmission, which is the etiological agent of this disease. Considering the need to know if T. cruzi can cause some pathology in the reproductive system of the Chagas disease vectors, we investigated the spermatogenesis of Triatoma infestans infected by T. cruzi through histological and cytogenetic analysis. Trypanosoma cruzi Bolivia strain infection was not pathogenic for the reproductive system of T. infestans, because all the analyzed males had normal spermatogenesis, with all phases (spermatocytogenesis, meiosis and spermiogenesis) happening without any change. Thus, we demonstrated that the presence of T. cruzi Bolivia strain does not have influence in the spermatogenesis of T. infestans and we suggest that the influences on reproductive system observed for other species were a result of the action of the parasite on gametogenesis of females.


Assuntos
Doença de Chagas/transmissão , Insetos Vetores/parasitologia , Espermatogênese/fisiologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/parasitologia , Interações Hospedeiro-Parasita , Insetos Vetores/fisiologia , Masculino , Triatoma/fisiologia
7.
Exp Parasitol ; 216: 107932, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32535113

RESUMO

Neglected tropical diseases, such as Chagas disease caused by the protozoa Trypanosoma cruzi, affect millions of people worldwide but lack effective treatments that are accessible to the entire population, especially patients with the debilitating chronic phase. The recognition of host cells, invasion and its intracellular replicative success are essential stages for progression of the parasite life cycle and the development of Chagas disease. It is predicted that programmed cell death pathways (apoptosis) would be activated in infected cells, either via autocrine secretion or mediated by cytotoxic immune cells. This process should play a key role in resolving infections by hindering the evolutionary success of the parasite. In this research, we performed assays to investigate the role of the lectin galectin-3 (Gal3) in parasite-host signaling pathways. Using cells with endogenous levels of Gal3 compared to Gal3-deficient cells (induced by RNA interference), we demonstrated that T. cruzi mediated the survival pathways and the subverted apoptosis through Gal3 promoting a pro-survival state in infected cells. Infected Gal3-depleted cells showed increased activation of caspase 3 and pro-apoptotic targets, such as poly (ADP-ribose) polymerase (PARP), and lower accumulation of anti-apoptotic proteins, such as c-IAP1, survivin and XIAP. During the early stages of infection, Gal3 translocates from the cytoplasm to the nucleus and must act in survival pathways. In a murine model of experimental infection, Gal3 knockout macrophages showed lower infectivity and viability. In vivo infection revealed a lower parasitemia and longer survival and an increased spleen cellularity in Gal3 knockout mice with consequences on the percentage of T lymphocytes (CD4+ CD11b+) and macrophages. In addition, cytokines such as IL-2, IL-4, IL-6 and TNF-α are increased in Gal3 knockout mice when compared to wild type genotype. These data demonstrate a Gal3-mediated complex interplay in the host cell, keeping infected cells alive long enough for infection and intracellular proliferation of new parasites. However, a continuous knowledge of these signaling pathways should contribute to a better understanding the mechanisms of cell death subversion that are promoted by protozoans in the pathophysiology of neglected diseases such as Chagas disease.


Assuntos
Apoptose/fisiologia , Doença de Chagas/parasitologia , Galectina 3/fisiologia , Trypanosoma cruzi/fisiologia , Análise de Variância , Animais , Western Blotting , Caspase 3/análise , Sobrevivência Celular , Doença de Chagas/mortalidade , Chlorocebus aethiops , Colorimetria , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Galectina 3/análise , Galectina 3/genética , Células HeLa , Humanos , Imunofenotipagem , Macrófagos Peritoneais/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parasitemia/mortalidade , Parasitemia/parasitologia , Fenótipo , Baço/patologia , Células Vero
8.
PLoS Negl Trop Dis ; 14(5): e0007980, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433643

RESUMO

Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most severe consequence of chronic Chagas disease and cannot be reversed solely by parasite load reduction. To prioritize new therapeutic targets, we unbiasedly interrogated the host signaling events in heart tissues isolated from a Chagas disease mouse model using quantitative, multiplexed proteomics. We defined the host response to infection at both the proteome and phospho-proteome levels. The proteome showed an increase in the immune response and a strong repression of several mitochondrial proteins. Complementing the proteome studies, the phospho-proteomic survey found an abundance of phospho-site alterations in plasma membrane and cytoskeletal proteins. Bioinformatic analysis of kinase activity provided substantial evidence for the activation of NDRG2 and JNK/p38 kinases during Chagas disease. A significant activation of DYRK2 and AMPKA2 and the inhibition of casein family kinases were also predicted. We concluded our analyses by linking the diseased heart proteome profile to known therapeutic interventions, uncovering a potential to target mitochondrial proteins, secreted immune effectors and core kinases for the treatment of chronic Chagas disease. Together, this study provides molecular insight into host proteome and phospho-proteome responses to T. cruzi infection in the heart for the first time, highlighting pathways that can be further validated for functional contributions to disease and suitability as drug targets.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Animais , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/parasitologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteoma/genética , Proteoma/metabolismo , Proteômica , Transdução de Sinais , Trypanosoma cruzi/fisiologia
9.
Infect Dis Poverty ; 9(1): 51, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393333

RESUMO

BACKGROUND: Chagas disease is endemic in Latin America and still represents an important public health problem in the region. Chronic cardiomyopathy is the most significant chronic form due to its association with morbidity and mortality. The last decade has seen increasing evidence that inflammatory cytokines and chemokines are responsible for the generation of inflammatory infiltrate and tissue damage, with chronic chagasic cardiomyopathy patients presenting a pro-inflammatory immune response. Although studies have evaluated the role of chemokines in experimental T. cruzi infection, few have addressed their systemic profile, especially for human infection and in aging populations. The present work aimed to use the data from a large population based study of older adults, conducted in an endemic area for Chagas disease, to examine the association between serum levels of cytokines and chemokines, T. cruzi infection and electrocardiogram (ECG) abnormality. METHODS: The present work evaluated serum levels of CCL2, CXCL9, CXCL10, CCL5, CXCL8, IL-1ß, IL-6, TNF, IL-12 and IL-10 by Flow Cytometric Bead Array assay (CBA) and the results expressed in pg/ml. The baseline survey started in January 1st 1997, with 1284 participants of an aged population-based cohort. Participants signed an informed consent at baseline and at each subsequent visit and authorized death certificate and medical records verification. RESULTS: Our results demonstrated that Chagas disease patients had higher serum levels of CXCL9, CXCL10 and IL-1ß and lower serum levels of CCL5 than non-infected subjects. Moreover, our data demonstrated that CXCL9 and CXCL10 increased in an age-dependent profile in Chagas disease patients. CONCLUSION: Together, this study provided evidences that serum biomarkers increase along the age continuum and may have potential implications for establishing clinical management protocols and therapeutic intervention in Chagas disease patients.


Assuntos
Envelhecimento , Doença de Chagas/metabolismo , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Trypanosoma cruzi/fisiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Brasil , Estudos de Coortes , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
J Vis Exp ; (157)2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32250348

RESUMO

Astrocytes and microglia are the most abundant glial cells. They are responsible for physiological support and homeostasis maintenance in the central nervous system (CNS). The increasing evidences of their involvement in the control of infectious diseases justify the emerging interest in the improvement of methodologies to isolate primary astrocytes and microglia in order to evaluate their responses to infections that affect the CNS. Considering the impact of Trypanosoma cruzi (T. cruzi) and Toxoplasma gondii (T. gondii) infection in the CNS, here we provide a method to extract, maintain, dissociate and infect murine astrocytes and microglia cells with protozoa parasites. Extracted cells from newborn cortices are maintained in vitro for 14 days with periodic differential media replacement. Astrocytes and microglia are obtained from the same extraction protocol by mechanical dissociation. After phenotyping by flow cytometry, cells are infected with protozoa parasites. The infection rate is determined by fluorescence microscopy at different time points, thus enabling the evaluation of differential ability of glial cells to control protozoan invasion and replication. These techniques represent simple, cheap and efficient methods to study the responses of astrocytes and microglia to infections, opening the field for further neuroimmunology analysis.


Assuntos
Astrócitos/citologia , Microglia/citologia , Doenças Parasitárias/patologia , Animais , Animais Recém-Nascidos , Astrócitos/parasitologia , Técnicas de Cultura de Células , Córtex Cerebral/citologia , Córtex Cerebral/parasitologia , Camundongos , Microglia/parasitologia , Doenças Parasitárias/parasitologia , Toxoplasma/fisiologia , Trypanosoma cruzi/fisiologia
11.
Acta Trop ; 205: 105433, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32126211

RESUMO

Triatomines are insect vectors of Trypanosoma cruzi¸ the etiological agent of Chagas disease. Several species belonging to the genus Rhodnius (Hemiptera: Reduviidae) have been reported inhabiting domestic and peridomestic environments in different regions of Latin America. However, behavioral and sensory ecology aspects related to their use of shelters have been poorly studied. The objective of the present study was to characterize how bug density, illumination and thigmotactic information affect the use of shelters by three species belonging to the Rhodnius prolixus species complex. We evaluated whether exposure to different insect densities affects the proportion of R. prolixus, Rhodnius robustus and Rhodnius neglectus that choose to stay inside a refuge. Besides, we evaluated whether absence of an illumination regime affects their tendency to hide in shelters. Our results showed that the proportion of individuals that remained outside the shelter increased with rising insect densities. Nevertheless, while R. prolixus only reacted by augmenting this proportion with the highest density tested, the other species showed significant increases already at lower densities. On the other hand, a significantly higher number of R. robustus stayed outside the shelter in the absence of a light cycle, while no change was induced for the other species. Thus, this study determined species-specific profiles of refuge exploitation defined by factors such as thigmotaxis and negative phototaxis. The differences observed among these Rhodnius species may impact their house colonization abilities, which seem to be critically affected by bug hiding performance during health service detection processes.


Assuntos
Doença de Chagas/transmissão , Rhodnius/fisiologia , Rhodnius/parasitologia , Animais , Comportamento Animal , Insetos Vetores/classificação , Especificidade da Espécie , Trypanosoma cruzi/fisiologia
12.
Trends Parasitol ; 36(4): 368-381, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32191851

RESUMO

To successfully infect, Trypanosoma cruzi evades and modulates the host immune response. T. cruzi calreticulin (TcCalr) is a multifunctional, endoplasmic reticulum (ER)-resident chaperone that, translocated to the external microenvironment, mediates crucial host-parasite interactions. TcCalr binds and inactivates C1 and mannose-binding lectin (MBL)/ficolins, important pattern- recognition receptors (PRRs) of the complement system. Using an apoptotic mimicry strategy, the C1-TcCalr association facilitates the infection of target cells. T. cruzi infection also seems to confer protection against tumorigenesis. Thus, recombinant TcCalr has important antiangiogenic properties, detected in vitro, ex vivo, and in ovum, most likely contributing at least in part, to its antitumor properties. Consequently, TcCalr is useful for investigating key issues of host-parasite interactions and possible new immunological/pharmacological interventions in the areas of Chagas' disease and experimental cancer.


Assuntos
Calreticulina/imunologia , Carcinogênese/imunologia , Doença de Chagas/complicações , Doença de Chagas/imunologia , Interações Hospedeiro-Parasita/imunologia , Neoplasias/etiologia , Trypanosoma cruzi/patogenicidade , Animais , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Humanos , Evasão da Resposta Imune/imunologia , Neoplasias/imunologia , Trypanosoma cruzi/fisiologia , Fatores de Virulência/imunologia
13.
Parasitol Res ; 119(6): 1829-1843, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32206887

RESUMO

The underlying pathogenic mechanisms of cardiomyopathy in Chagas disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the present study employed three murine models of chronic Trypanosoma cruzi infection: (1) aP2-RIDα/ß transgenic mice (RID mice; an adipose tissue model which express a gain-of-function potent anti-inflammatory activity), (2) allograft inflammatory factor-1 knockout mice (Aif1-/-), and (3) a Swiss outbred mice. RID mice and non-transgenic mice (wild type, WT) were infected with blood trypomastigotes of Brazil strain. During the acute stage of infection, RID mice had lower parasitemia, lower heart inflammation, and a decrease in the relative distribution of parasite load from cardiac muscle tissue toward epididymal fat. Nevertheless, comparable profiles of myocardial inflammatory infiltrates and relative distribution of parasite load were observed among RID and WT at the chronic stage of infection. Aif1-/- and Aif1+/+ mice were infected with bloodstream trypomastigotes of Tulahuen strain and fed with high-fat diet (HFD) or regular diet (RD). Interestingly, Aif1+/+ HFD infected mice showed the highest mortality. Swiss mice infected with blood trypomastigotes of Berenice-78 strain on a HFD had higher levels of TNFα and more inflammation in their heart tissue than infected mice fed a RD. These various murine models implicate adipocytes in the pathogenesis of chronic Chagas disease and suggest that HFD can lead to a significant increase in the severity of parasite-induced chronic cardiac damage. Furthermore, these data implicate adipocyte TLR4-, TNFα-, and IL-1ß-mediated signaling in pro-inflammatory pathways and Aif-1 gene expression in the development of chronic Chagas disease.


Assuntos
Cardiomiopatia Chagásica/patologia , Doença de Chagas/complicações , Dieta Hiperlipídica , Trypanosoma cruzi , Animais , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Feminino , Coração/parasitologia , Inflamação/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/patologia , Carga Parasitária , Trypanosoma cruzi/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
14.
Acta Trop ; 205: 105392, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32061627

RESUMO

There are 8 million people with Chagas disease worldwide and in El Salvador approximately 39% of the population is at risk of contracting the disease. One of the principal challenges in mitigating Chagas is evaluating the role of the vector ecology of triatomine species in the transmission of the Trypanosoma cruzi parasite in anthropogenically modified habitats, where new patterns of transmission frequently arise. Field studies of triatomine vector ecology in El Salvador have largely focused on describing parameters that contribute to infestation patterns, which may themselves be rooted in the morphological variability that exists in triatomine populations. The objective of this study was to evaluate the morphology of the vector species Triatoma dimidiata with respect to the characteristics of the ecological landscape the vector inhabits throughout El Salvador. We used image analyses to evaluate T. dimidiata morphological variability and then used Geographic Information Systems to intersect the morphological point-data with map layers containing different environmental characteristics. Our study found that the variation in the size, shape, and coloration of T. dimidiata varied in relation to elevation, Holdridge life zone, soil type and land use. We further characterize the local morphological adaptations of T. dimidiata with respect to the local ecological, biological, and geographical conditions in El Salvador. We suggest that future studies consider a molecular exploration of local T. dimidiata species complex in El Salvador, especially since morphological studies of triatomine species complex have found that variability correlate with the genetic variability of the population.


Assuntos
Distribuição Animal , Doença de Chagas/transmissão , Ecossistema , Insetos Vetores/fisiologia , Triatoma/fisiologia , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/epidemiologia , El Salvador/epidemiologia , Insetos Vetores/parasitologia , Triatoma/parasitologia , Trypanosoma cruzi/genética
15.
Molecules ; 25(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963596

RESUMO

Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of 3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in the 3-step synthetic procedure. According to recommended guidelines, the whole cell-based screening methodology was utilized that allowed for the simultaneous use of both parasite forms responsible for human infection. The majority of the tested compounds displayed promising anti-Trypanosoma cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the reference drug, Benznidazole.


Assuntos
Flavanonas/síntese química , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Flavanonas/química , Flavanonas/farmacologia , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Nitrofuranos , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/fisiologia
16.
Exp Parasitol ; 210: 107834, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978394

RESUMO

Studies suggest that the dose of the standard benznidazole (BNZ) treatment regimen might be too high. We investigated the efficacy of BNZ 20 and 40 mg/kg/day compared with standard dose (100 mg/kg/day) to induce cure in mice infected with Trypanosoma cruzi Y strain in the acute and chronic phases of Chagas' disease. Our findings indicate that an experimental treatment with a BNZ low-dose (40 mg/kg/day) is similarly effective as the usual dose in the chronic mice model (100% of cure). In addition, the treatment in the chronic model of Chagas' disease presented better results than the acute model and colon appears to be a key tissue when it comes to evaluating treatment efficacy compared to blood and heart. Therefore, our data suggest the reconsideration of the current therapy, mainly in the chronic phase of the disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/administração & dosagem , Tripanossomicidas/administração & dosagem , Doença Aguda , Animais , Sangue/parasitologia , Doença de Chagas/parasitologia , Doença Crônica , Colo/parasitologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Feminino , Coração/parasitologia , Imunossupressão , Camundongos , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Nitroimidazóis/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Trypanosoma cruzi/fisiologia
17.
Parasitol Res ; 119(1): 333-337, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31788770

RESUMO

Chagas disease (CD) is a tropical zoonosis caused by the protozoan Trypanosoma cruzi. Severe autonomic dysfunction like reduced cardiac catecholamine-containing or acetylcholinesterase-positive innervation have been reported in CD. Renin-angiotensin system (RAS) seems to participate in the regulation of adrenal catecholamine secretion by adrenal medullary chromaffin cells, which might be dependent of nitric oxide (NO) pathways. To investigate the levels of RAS components in the adrenal gland during the acute infection with Y strain T. cruzi and in response to acute administration of an inhibitor of the enzyme NO synthase, L-NAME. Male Holtzman rats were inoculated intraperitoneally with Y strain T. cruzi and received L-NAME or tap water from one day before the infection until 13 or 17 days post-inoculation (dpi). The concentration of RAS molecules in the adrenal tissue was evaluated by ELISA immunoassay. Angiotensin converting enzyme 1 (ACE1) levels were significantly lower at 17 dpi when compared to 13 dpi. No significant differences were found compared with baseline, and no changes were detected in adrenal tissue levels of angiotensin converting enzyme 2 (ACE2), angiotensin II, or angiotensin-(1-7). Moreover, the treatment with L-NAME did not influence the levels of RAS components in adrenal tissue during the course of T. cruzi infection. We provided the first evidence that levels of RAS molecules change in the adrenal gland during acute phase of T. cruzi infection. Future studies are necessary to fully address the role of NO in RAS-associated adrenal gland function in CD.


Assuntos
Glândulas Suprarrenais/metabolismo , Doença de Chagas/metabolismo , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/fisiologia , Trypanosoma cruzi/fisiologia , Animais , Modelos Animais de Doenças , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Acta Trop ; 202: 105273, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31734265

RESUMO

Among the many environmental challenges the parasite Trypanosoma cruzi has to overcome to complete its life cycle through different hosts, oxidative stress plays a central role. Different stages of this parasite encounter distinct sources of oxidative stress, such as the oxidative burst of the immune system, or the Heme released from hemoglobin degradation in the triatomine's midgut. Also, the redox status of the surroundings functions as a signal to the parasite, triggering processes coupled to differentiation or proliferation. Intracellular second messengers, like cAMP, are responsible for the transduction of environmental queues and initiating cellular processes accordingly. In trypanosomatids cAMP is involved in a variety of processes, including proliferation, differentiation, osmoregulation and quorum sensing. Trypanosomatid phosphodiesterases (PDE) show atypical pharmacological properties and some have been involved in key processes for the survival of the parasites, which validates them as attractive therapeutic targets. Our work here shows that cAMP modulates different processes according to parasite stage. Epimastigotes become more resistant to oxidative stress when pre-treated with cAMP analogs, while in trypomastigotes an increase in intracellular cAMP doesn't seem to aid in this response, although it does increase the number of amastigotes obtained 48 h after infection, compared to the control group. Also, we show that TcrPDEA1, a functionally enigmatic phosphodiesterase with very high Km, is involved in the epimastigotes response to oxidative stress.


Assuntos
AMP Cíclico/metabolismo , Citoplasma/metabolismo , Trypanosoma cruzi/fisiologia , Animais , Chlorocebus aethiops , Estágios do Ciclo de Vida , Oxirredução , Células Vero
20.
Acta Trop ; 202: 105262, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31706861

RESUMO

Chagas disease (CD), caused by Trypanosoma cruzi, is the main parasitic disease in the Western Hemisphere, with an increasing number of cases, especially in non-endemic regions. The disease is characterized by cardiomegaly and mega viscera, nevertheless, the clinical outcome is hard to predict, underscoring the need for further research into the pathophysiology of CD. Even though most basic and translational research involving CD is performed using in vivo models, in vitro models arise as an ethical, rapidly evolving, and physiologically relevant alternative for CD research. In the present review, we discuss the past and recent in vitro models available to study the host-parasite interface in cardiac and intestinal CD, critically analyzing the possibilities and limitations of state-of-the-art alternatives for the CD host-parasite investigation.


Assuntos
Doença de Chagas/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Células Cultivadas , Interações Hospedeiro-Parasita , Humanos
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