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1.
Front Immunol ; 13: 975106, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439149

RESUMO

The involvement of the central nervous system (CNS) during human acute and chronic Chagas disease (CD) has been largely reported. Meningoencephalitis is a frequent finding during the acute infection, while during chronic phase the CNS involvement is often accompanied by behavioral and cognitive impairments. In the same vein, several studies have shown that rodents infected with Trypanosoma cruzi (T. cruzi) display behavior abnormalities, accompanied by brain inflammation, in situ production of pro-inflammatory cytokines and parasitism in diverse cerebral areas, with involvement of microglia, macrophages, astrocytes, and neurons. However, the mechanisms used by the parasite to reach the brain remain now largely unknown. Herein we discuss the evidence unravelling the CNS involvement and complexity of neuroimmune interactions that take place in acute and chronic CD. Also, we provide some clues to hypothesize brain infections routes in human and experimental acute CD following oral infection by T. cruzi, an infection route that became a major CD related public health issue in Brazil.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Humanos , Trypanosoma cruzi/fisiologia , Sistema Nervoso Central , Astrócitos , Encéfalo/parasitologia
2.
Front Cell Infect Microbiol ; 12: 800395, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35402296

RESUMO

During the acute phase of Chagas disease, Trypanosoma cruzi circulation through the bloodstream leads to high tissue parasitism in the host. In primary lymphoid organs, progenitor cell reduction paralleled transient immunosuppression. Herein we showed that acute oral infection in mice promotes diffuse parasitism in bone marrow cells at 14 and 21 days post-infection (dpi), with perivascular regions, intravascular regions, and regions near the bone being target sites of parasite replication. Phenotypic analysis of hematopoietic differentiation in the bone marrow of infected mice showed that the cell number in the tissue is decreased (lineage-negative and lineage-positive cells). Interestingly, analysis of hematopoietic branching points showed that hematopoietic stem and progenitor cells (HSPCs) were significantly increased at 14 dpi. In addition, the pool of progenitors with stem plasticity (HSC-MPP3), as well as multipotent progenitors (MPPs) such as MPP4, also showed this pattern of increase. In contrast, subsequent progenitors that arise from MPPs, such as common lymphoid progenitors (CLPs), lymphoid-primed MPPs (LMPPs), and myeloid progenitors, were not enhanced; conversely, all presented numeric decline. Annexin V staining revealed that cell death increase in the initial hematopoietic branching point probably is not linked to CLPs and that myeloid progenitors decreased at 14 and 21 dpi. In parallel, our investigation provided clues that myeloid progenitor decrease could be associated with an atypical expression of Sca-1 in this population leading to a remarkable increase on LSK-like cells at 14 dpi within the HSPC compartment. Finally, these results led us to investigate HSPC presence in the spleen as a phenomenon triggered during emergency hematopoiesis due to mobilization or expansion of these cells in extramedullary sites. Splenocyte analysis showed a progressive increase in HSPCs between 14 and 21 dpi. Altogether, our study shows that the bone marrow is a target tissue in T. cruzi orally infected mice, leading to a hematopoietic disturbance with LSK-like cell bias accounting on HSPCs possibly affecting myeloid progenitor numbers. The LMPP and CLP reduction converges with defective thymocyte development. Lastly, it is tempting to speculate that the extramedullary hematopoiesis seen in the spleen is a mechanism involved in the hematological maintenance reported during the acute phase of oral T. cruzi infection.


Assuntos
Doença de Chagas , Hematopoese Extramedular , Trypanosoma cruzi , Animais , Diferenciação Celular , Linhagem da Célula , Hematopoese/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
3.
PLoS Negl Trop Dis ; 14(12): e0008969, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33347472

RESUMO

CD8 T cells are regarded as pivotal players in both immunoprotection and immunopathology following Trypanosoma cruzi infection. Previously, we demonstrated the expansion of CD8+ T lymphocytes in the spleen of T. cruzi-infected mice under treatment with benznidazole (N-benzyl-2-nitroimidazole acetamide; Bz), a drug available for clinical therapy. This finding underlies the concept that the beneficial effects of Bz on controlling acute T. cruzi infection are related to a synergistic process between intrinsic trypanocidal effect and indirect triggering of the active immune response. In the present study, we particularly investigated the effect of Bz treatment on the CD8+ T cell subset following T. cruzi infection. Herein we demonstrated that, during acute T. cruzi infection, Bz treatment reduces and abbreviates the parasitemia, but maintains elevated expansion of CD8+ T cells. Within this subset, a remarkable group of CD8low cells was found in both Bz-treated and non-treated infected mice. In Bz-treated mice, early pathogen control paralleled the lower frequency of recently activated CD8low cells, as ascertained by CD69 expression. However, the CD8low subset sustains significant levels of CD44highCD62Llow and CD62LlowT-bethigh effector memory T cells, in both Bz-treated and non-treated infected mice. These CD8low cells also comprise the main group of spontaneous interferon (IFN)-γ-producing CD8+ T cells. Interestingly, following in vitro anti-CD3/CD28 stimulation, CD8+ T cells from Bz-treated T. cruzi-infected mice exhibited higher frequency of IFN-γ+ cells, which bear mostly a CD8low phenotype. Altogether, our results point to the marked presence of CD8low T cells that arise during acute T. cruzi infection, with Bz treatment promoting their significant expansion along with a potential effector program for high IFN-γ production.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Doença Aguda , Animais , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/parasitologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Trypanosoma cruzi/genética
4.
Front Immunol ; 11: 1838, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983098

RESUMO

Chagas disease, caused by the protozoan parasite T. cruzi, is a prevalent parasitic disease in Latin America. Presently, it is spreading around the world by human migration, thus representing a new global health issue. Chronically infected individuals reveal a dissimilar disease progression: while nearly 60% remain without apparent disease for life, 30% develop life-threatening pathologies, such as chronic chagasic cardiomyopathy (CCC) or megaviscerae. Inflammation driven by parasite persistence seems to be involved in the pathophysiology of the disease. However, there is also evidence of the occurrence of autoimmune events, mainly caused by molecular mimicry and bystander activation. In experimental models of disease, is well-established that T. cruzi infects the thymus and causes locally profound structural and functional alterations. The hallmark is a massive loss of CD4+CD8+ double positive (DP) thymocytes, mainly triggered by increased levels of glucocorticoids, although other mechanisms seem to act simultaneously. Thymic epithelial cells (TEC) exhibited an increase in extracellular matrix deposition, which are related to thymocyte migratory alterations. Moreover, medullary TEC showed a decreased expression of AIRE and altered expression of microRNAs, which might be linked to a disrupted negative selection of the T-cell repertoire. Also, almost all stages of thymocyte development are altered, including an abnormal output of CD4-CD8- double negative (DN) and DP immature and mature cells, many of them carrying prohibited TCR-Vß segments. Evidence has shown that DN and DP cells with an activated phenotype can be tracked in the blood of humans with chronic Chagas disease and also in the secondary lymphoid organs and heart of infected mice, raising new questions about the relevance of these populations in the pathogenesis of Chagas disease and their possible link with thymic alterations and an immunoendocrine imbalance. Here, we discuss diverse molecular mechanisms underlying thymic abnormalities occurring during T. cruzi infection and their link with CCC, which may contribute to the design of innovative strategies to control Chagas disease pathology.


Assuntos
Doença de Chagas/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Epiteliais/imunologia , Humanos , Camundongos
5.
Mem Inst Oswaldo Cruz ; 115: e190364, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130371

RESUMO

Oral transmission of Chagas disease has been increasing in Latin American countries. The present study aimed to investigate changes in hepatic function, coagulation factor levels and parasite load in human acute Chagas disease (ACD) secondary to oral Trypanosoma cruzi transmission. Clinical and epidemiological findings of 102 infected individuals attended in the State of Pará from October 2013 to February 2016 were included. The most common symptoms were fever (98%), asthenia (83.3%), face and limb edema (80.4%), headache (74.5%) and myalgia (72.5%). The hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of 30 ACD patients were higher compared with controls, and this increase was independent of the treatment with benznidazole. Moreover, ACD individuals had higher plasma levels of activated protein C and lower levels of factor VII of the coagulation cascade. Patients with the highest parasite load had also the most increased transaminase levels. Also, ALT and AST were associated moderately (r = 0.429) and strongly (r = 0.595) with parasite load respectively. In conclusion, the present study raises the possibility that a disturbance in coagulation and hepatic function may be linked to human ACD.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Doença de Chagas/fisiopatologia , Fator VIIa/análise , Fígado/fisiopatologia , Proteína C/análise , Doença Aguda , Adulto , Biomarcadores/sangue , Brasil/epidemiologia , Estudos de Casos e Controles , Doença de Chagas/sangue , Doença de Chagas/enzimologia , Doença de Chagas/transmissão , Feminino , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Carga Parasitária , Estudos Prospectivos
6.
Front Immunol ; 10: 1073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139194

RESUMO

Oral transmission of Trypanosoma cruzi, the etiologic agent of Chagas disease, is presently the most important route of infection in Brazilian Amazon. Other South American countries have also reported outbreaks of acute Chagas disease associated with food consumption. A conspicuous feature of this route of transmission is presenting symptoms such as facial and lower limbs edema, in some cases bleeding manifestations and risk of thromboembolism are evident. Notwithstanding, studies that address this route of infection are largely lacking regarding its pathogenesis and, more specifically, the crosstalk between immune and hemostatic systems. Here, BALB/c mice were orally infected with metacyclic trypomastigotes of T. cruzi Tulahuén strain and used to evaluate the cytokine response, primary and secondary hemostasis during acute T. cruzi infection. When compared with control uninfected animals, orally infected mice presented higher pro-inflammatory cytokine (TNF-α, IFN-γ, and IL-6) serum levels. The highest concentrations were obtained concomitantly to the increase of parasitemia, between 14 and 28 days post-infection (dpi). Blood counts in the oral infected group revealed concomitant leukocytosis and thrombocytopenia, the latter resulting in increased bleeding at 21 dpi. Hematological changes paralleled with prolonged activated partial thromboplastin time, Factor VIII consumption and increased D-dimer levels, suggest that oral T. cruzi infection relies on disseminated intravascular coagulation. Remarkably, blockade of the IL-6 receptor blunted hematological abnormalities, revealing a critical role of IL-6 in the course of oral infection. These results unravel that acute T. cruzi oral infection results in significant alterations in the hemostatic system and indicates the relevance of the crosstalk between inflammation and hemostasis in this parasitic disease.


Assuntos
Doença de Chagas/imunologia , Hemostasia , Interleucina-6/fisiologia , Doença Aguda , Animais , Doença de Chagas/sangue , Doença de Chagas/complicações , Citocinas/biossíntese , Coagulação Intravascular Disseminada/etiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/imunologia , Transdução de Sinais , Trombocitopenia/etiologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-29963015

RESUMO

T cell response plays an essential role in the host resistance to infection by the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. This infection is often associated with multiple manifestations of T cell dysfunction, both during the acute and the chronic phases of disease. Additionally, the normal development of T cells is affected. As seen in animal models of Chagas disease, there is a strong thymic atrophy due to massive death of CD4+CD8+ double-positive cells by apoptosis and an abnormal escape of immature and potentially autoreactive thymocytes from the organ. Furthermore, an increase in the release of corticosterone triggered by T. cruzi-driven systemic inflammation is strongly associated with the alterations seen in the thymus of infected animals. Moreover, changes in the levels of other hormones, including growth hormone, prolactin, and testosterone are also able to contribute to the disruption of thymic homeostasis secondary to T. cruzi infection. In this review, we discuss the role of hormonal circuits involved in the normal T cell development and trafficking, as well as their role on the thymic alterations likely related to the peripheral T cell disturbances largely reported in both chagasic patients and animal models of Chagas disease.

8.
Brain Behav Immun ; 65: 284-295, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28666938

RESUMO

Earlier studies from our laboratory demonstrated that acute experimental Trypanosoma cruzi infection promotes an intense inflammation along with a sepsis-like dysregulated adrenal response characterized by normal levels of ACTH with raised glucocorticoid secretion. Inflammation was also known to result in adrenal cell apoptosis, which in turn may influence HPA axis uncoupling. To explore factors and pathways which may be involved in the apoptosis of adrenal cells, together with its impact on the functionality of the gland, we carried out a series of studies in mice lacking death receptors, such as TNF-R1 (C57BL/6-Tnfrsf1a tm1Imx or TNF-R1-/-) or Fas ligand (C57BL/6 Fas-deficient lpr mice), undergoing acute T. cruzi infection. Here we demonstrate that the late hypercorticosterolism seen in C57BL/6 mice during acute T. cruzi infection coexists with and hyperplasia and hypertrophy of zona fasciculata, paralleled by increased number of apoptotic cells. Apoptosis seems to be mediated mainly by the type II pathway of Fas-mediated apoptosis, which engages the mitochondrial pathway of apoptosis triggering the cytochrome c release to increase caspase-3 activation. Fas-induced apoptosis of adrenocortical cells is also related with an exacerbated production of intra-adrenal cytokines that probably maintain the late supply of adrenal hormones during host response. Present results shed light on the molecular mechanisms dealing with these phenomena which are crucial not only for the development of interventions attempting to avoid adrenal dysfunction, but also for its wide occurrence in other infectious-based critical illnesses.


Assuntos
Córtex Suprarrenal/fisiopatologia , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Receptor fas/fisiologia , Córtex Suprarrenal/microbiologia , Animais , Apoptose/imunologia , Apoptose/fisiologia , Caspase 3/metabolismo , Citocinas/metabolismo , Proteína Ligante Fas/metabolismo , Proteína Ligante Fas/fisiologia , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/metabolismo , Receptor fas/metabolismo
9.
PLoS Negl Trop Dis ; 11(4): e0005507, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28379959

RESUMO

Oral transmission of Trypanosoma cruzi, the causative agent of Chagas disease, is the most important route of infection in Brazilian Amazon and Venezuela. Other South American countries have also reported outbreaks associated with food consumption. A recent study showed the importance of parasite contact with oral cavity to induce a highly severe acute disease in mice. However, it remains uncertain the primary site of parasite entry and multiplication due to an oral infection. Here, we evaluated the presence of T. cruzi Dm28c luciferase (Dm28c-luc) parasites in orally infected mice, by bioluminescence and quantitative real-time PCR. In vivo bioluminescent images indicated the nasomaxillary region as the site of parasite invasion in the host, becoming consistently infected throughout the acute phase. At later moments, 7 and 21 days post-infection (dpi), luminescent signal is denser in the thorax, abdomen and genital region, because of parasite dissemination in different tissues. Ex vivo analysis demonstrated that the nasomaxillary region, heart, mandibular lymph nodes, liver, spleen, brain, epididymal fat associated to male sex organs, salivary glands, cheek muscle, mesenteric fat and lymph nodes, stomach, esophagus, small and large intestine are target tissues at latter moments of infection. In the same line, amastigote nests of Dm28c GFP T. cruzi were detected in the nasal cavity of 6 dpi mice. Parasite quantification by real-time qPCR at 7 and 21 dpi showed predominant T. cruzi detection and expansion in mouse nasal cavity. Moreover, T. cruzi DNA was also observed in the mandibular lymph nodes, pituitary gland, heart, liver, small intestine and spleen at 7 dpi, and further, disseminated to other tissues, such as the brain, stomach, esophagus and large intestine at 21 dpi. Our results clearly demonstrated that oral cavity and adjacent compartments is the main target region in oral T. cruzi infection leading to parasite multiplication at the nasal cavity.


Assuntos
Estruturas Animais/parasitologia , Doença de Chagas/transmissão , Boca/parasitologia , Parasitemia/diagnóstico , Trypanosoma cruzi/isolamento & purificação , Animais , Chlorocebus aethiops , Modelos Animais de Doenças , Medições Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células Vero
10.
PLoS Negl Trop Dis ; 9(6): e0003849, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26090667

RESUMO

Oral transmission of Chagas disease has been documented in Latin American countries. Nevertheless, significant studies on the pathophysiology of this form of infection are largely lacking. The few studies investigating oral route infection disregard that inoculation in the oral cavity (Oral infection, OI) or by gavage (Gastrointestinal infection, GI) represent different infection routes, yet both show clear-cut parasitemia and heart parasitism during the acute infection. Herein, BALB/c mice were subjected to acute OI or GI infection using 5x10(4) culture-derived Trypanosoma cruzi trypomastigotes. OI mice displayed higher parasitemia and mortality rates than their GI counterparts. Heart histopathology showed larger areas of infiltration in the GI mice, whereas liver lesions were more severe in the OI animals, accompanied by higher Alanine Transaminase and Aspartate Transaminase serum contents. A differential cytokine pattern was also observed because OI mice presented higher pro-inflammatory cytokine (IFN-γ, TNF) serum levels than GI animals. Real-time PCR confirmed a higher TNF, IFN-γ, as well as IL-10 expression in the cardiac tissue from the OI group compared with GI. Conversely, TGF-ß and IL-17 serum levels were greater in the GI animals. Immunolabeling revealed macrophages as the main tissue source of TNF in infected mice. The high mortality rate observed in the OI mice paralleled the TNF serum rise, with its inhibition by an anti-TNF treatment. Moreover, differences in susceptibility between GI versus OI mice were more clearly related to the host response than to the effect of gastric pH on parasites, since infection in magnesium hydroxide-treated mice showed similar results. Overall, the present study provides conclusive evidence that the initial site of parasite entrance critically affects host immune response and disease outcome. In light of the occurrence of oral Chagas disease outbreaks, our results raise important implications in terms of the current view of the natural disease course and host-parasite relationship.


Assuntos
Doença de Chagas/transmissão , Citocinas/metabolismo , Trypanosoma cruzi , Animais , Doença de Chagas/imunologia , Doença de Chagas/mortalidade , Citocinas/sangue , Citocinas/genética , Regulação da Expressão Gênica/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/patologia , Parasitemia/imunologia , Parasitemia/mortalidade , Parasitemia/transmissão , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/patogenicidade
11.
Front Immunol ; 4: 216, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23898334

RESUMO

Acute Chagas disease is characterized by a systemic infection that leads to the strong activation of the adaptive immune response. Outbreaks of oral contamination by the infective protozoan Trypanosoma cruzi are frequent in Brazil and other Latin American countries, and an increased severity of clinical manifestations and mortality is observed in infected patients. These findings have elicited questions about the specific responses triggered after T. cruzi entry via mucosal sites, possibly modulating local immune mechanisms, and further impacting regional and systemic immunity. Here, we provide evidence for the existence of differential lymphoid organ responses in experimental models of acute T. cruzi infection.

12.
Immunotherapy ; 5(6): 573-6, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23725281

RESUMO

Evaluation of: Nobrega C, Nunes-Alves C, Cerqueira-Rodrigues B et al. T cells home to the thymus and control infection. J. Immunol. 190, 1646-1658 (2013). It is well documented that the thymus is a target organ for a large variety of pathogens (virus, bacteria, fungi and protozoa). Moreover, the presence of pathogen-derived antigens in the thymus of infected mice seems to interfere with the capacity of mature T cells to respond to the invading organism. In this way, Nobrega and colleagues demonstrated in 2010 that Mycobacterium avium infection in the thymus leads to the appearance of differentiated T cells tolerogenic for bacterial antigens. In the present and elegant study, the same group demonstrates that T-cell recirculation from the periphery to the thymus is a mechanism that allows the immune system to respond to thymic infection. A Mycobacterium-infected thymus increases the production of Th1-effector chemokines, such as CXCL9 and CXCL10, which in turn recruit CXCR3(+) peripheral T cells involved in intrathymic bacterial control. Taken together, these findings may represent an important issue of the host response, in terms of different pathogens able to infect the thymus.


Assuntos
Movimento Celular/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/microbiologia , Timo/imunologia , Timo/microbiologia , Animais
13.
Microbes Infect ; 15(5): 365-74, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23481510

RESUMO

In experimental Trypanosoma cruzi infections, severe thymic atrophy leads to release of activated CD4(+)CD8(+) double-positive (DP) T cells to the periphery. In humans, activated DP T cells are found in the blood in association with severe cardiac forms of human chronic Chagas disease. The mechanisms underlying the premature thymocyte release during the chagasic thymic atrophy remain elusive. We tested whether the migratory properties of intrathymic thymocytes are modulated by the parasite trans-sialidase (TS). We found that TS affected the dynamics of thymocytes undergoing intrathymic maturation, and these changes were accompanied by an increase in the number of recent DP thymic emigrants in the peripheral lymphoid organs. We demonstrated that increased percentages of blood DP T cell subsets were associated with augmented antibody titers against TS in chagasic patients with chronic cardiomyopathy. In vitro studies showed that TS was able to activate the MAPK pathway and actin filament mobilization in thymocytes. These effects were correlated with its ability to modulate the adhesion of thymocytes to thymic epithelial cells and their migration toward extracellular matrix. These findings point to effects of TS that could influence the escape of immature thymocytes in Chagas disease.


Assuntos
Adesão Celular , Movimento Celular , Fibronectinas/metabolismo , Glicoproteínas/metabolismo , Interações Hospedeiro-Patógeno , Neuraminidase/metabolismo , Timócitos/fisiologia , Trypanosoma cruzi/enzimologia , Adulto , Animais , Doença de Chagas/imunologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Feminino , Humanos , Subpopulações de Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
14.
J Leukoc Biol ; 93(2): 227-34, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23159925

RESUMO

Trypanosoma cruzi acute infection leads to thymic atrophy, largely as a result of death of immature DP T cells. In a second vein, the glucocorticoid hormone imbalance promotes DP T cell apoptosis in infected mice. Herein, we assessed the involvement of caspase signaling in thymocyte death during T. cruzi acute infection. BALB/c mice were infected i.p. with 10(2) trypomastigote forms of T. cruzi and analyzed from 7 to 19 dpi. Thymocyte apoptosis was observed in early stages of infection, increasing along with time postinfection. Immature DN and DP as well as CD4(+) and CD8(+) thymocytes from infected mice showed increased activation of caspase-8, -9, and -3. In vitro treatment of thymocytes from infected mice with a general caspase inhibitor or the combination of caspase-8- and caspase-9-specific inhibitors increased the number of living thymocytes. Intrathymic injection of the general caspase inhibitor, but not caspase-8 or -9 inhibitors individually, prevented thymic atrophy and thymocyte depletion in infected mice. Moreover, blockade of glucocorticoid receptor activity with RU486 prevented DP thymocyte apoptosis, together with caspase-8 and -9 activation. These findings indicate that DP T cell apoptosis following experimental T. cruzi acute infection is dependent on glucocorticoid stimulation, promoting caspase-8 and -9 activation.


Assuntos
Caspase 8/metabolismo , Caspase 9/metabolismo , Doença de Chagas/enzimologia , Linfócitos T/patologia , Animais , Apoptose , Doença de Chagas/imunologia , Doença de Chagas/patologia , Citometria de Fluxo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/enzimologia , Linfócitos T/parasitologia , Timo/enzimologia , Timo/imunologia , Timo/patologia , Trypanosoma cruzi/imunologia
15.
J Trop Med ; 2012: 747185, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22505943

RESUMO

The comprehension of the immune responses in infectious diseases is crucial for developing novel therapeutic strategies. Here, we review current findings on the dynamics of lymphocyte subpopulations following experimental acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. In the thymus, although the negative selection process of the T-cell repertoire remains operational, there is a massive thymocyte depletion and abnormal release of immature CD4(+)CD8(+) cells to peripheral lymphoid organs, where they acquire an activated phenotype similar to activated effector or memory T cells. These cells apparently bypassed the negative selection process, and some of them are potentially autoimmune. In infected animals, an atrophy of mesenteric lymph nodes is also observed, in contrast with the lymphocyte expansion in spleen and subcutaneous lymph nodes, illustrating a complex and organ specific dynamics of lymphocyte subpopulations. Accordingly, T- and B-cell activation is seen in subcutaneous lymph nodes and spleen, but not in mesenteric lymph nodes. Lastly, although the function of peripheral CD4(+)CD8(+) T-cell population remains to be defined in vivo, their presence may contribute to the immunopathological events found in both murine and human Chagas disease.

16.
J Parasitol Res ; 2012: 574020, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22518275

RESUMO

The thymus is a primary lymphoid organ in which bone marrow-derived T-cell precursors undergo differentiation, leading to migration of positively selected thymocytes to the T-cell-dependent areas of secondary lymphoid organs. This organ can undergo atrophy, caused by several endogenous and exogenous factors such as ageing, hormone fluctuations, and infectious agents. This paper will focus on emerging data on the thymic atrophy caused by infectious agents. We present data on the dynamics of thymus lymphocytes during acute Trypanosoma cruzi infection, showing that the resulting thymus atrophy comprises the abnormal release of thymic-derived T cells and may have an impact on host immune response.

17.
PLoS Negl Trop Dis ; 5(8): e1268, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21858238

RESUMO

Extrathymic CD4+CD8+ double-positive (DP) T cells are increased in some pathophysiological conditions, including infectious diseases. In the murine model of Chagas disease, it has been shown that the protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironment and the lymphoid compartment. In the acute phase, this results in a severe atrophy of the organ and early release of DP cells into the periphery. To date, the effect of the changes promoted by the parasite infection on thymic central tolerance has remained elusive. Herein we show that the intrathymic key elements that are necessary to promote the negative selection of thymocytes undergoing maturation during the thymopoiesis remains functional during the acute chagasic thymic atrophy. Intrathymic expression of the autoimmune regulator factor (Aire) and tissue-restricted antigen (TRA) genes is normal. In addition, the expression of the proapoptotic Bim protein in thymocytes was not changed, revealing that the parasite infection-induced thymus atrophy has no effect on these marker genes necessary to promote clonal deletion of T cells. In a chicken egg ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic system, the administration of OVA peptide into infected mice with thymic atrophy promoted OVA-specific thymocyte apoptosis, further indicating normal negative selection process during the infection. Yet, although the intrathymic checkpoints necessary for thymic negative selection are present in the acute phase of Chagas disease, we found that the DP cells released into the periphery acquire an activated phenotype similar to what is described for activated effector or memory single-positive T cells. Most interestingly, we also demonstrate that increased percentages of peripheral blood subset of DP cells exhibiting an activated HLA-DR+ phenotype are associated with severe cardiac forms of human chronic Chagas disease. These cells may contribute to the immunopathological events seen in the Chagas disease.


Assuntos
Atrofia/patologia , Antígenos CD4/análise , Antígenos CD8/análise , Doença de Chagas/complicações , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/imunologia , Timo/patologia , Adulto , Animais , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/patogenicidade
18.
PLoS Negl Trop Dis ; 3(7): e417, 2009 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-19582140

RESUMO

Following infection, lymphocytes expand exponentially and differentiate into effector cells to control infection and coordinate the multiple effector arms of the immune response. Soon after this expansion, the majority of antigen-specific lymphocytes die, thus keeping homeostasis, and a small pool of memory cells develops, providing long-term immunity to subsequent reinfection. The extent of infection and rate of pathogen clearance are thought to determine both the magnitude of cell expansion and the homeostatic contraction to a stable number of memory cells. This straight correlation between the kinetics of T cell response and the dynamics of lymphoid tissue cell numbers is a constant feature in acute infections yielded by pathogens that are cleared during the course of response. However, the regional dynamics of the immune response mounted against pathogens that are able to establish a persistent infection remain poorly understood. Herein we discuss the differential lymphocyte dynamics in distinct central and peripheral lymphoid organs following acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. While the thymus and mesenteric lymph nodes undergo a severe atrophy with massive lymphocyte depletion, the spleen and subcutaneous lymph nodes expand due to T and B cell activation/proliferation. These events are regulated by cytokines, as well as parasite-derived moieties. In this regard, identifying the molecular mechanisms underlying regional lymphocyte dynamics secondary to T. cruzi infection may hopefully contribute to the design of novel immune intervention strategies to control pathology in this infection.


Assuntos
Doença de Chagas/imunologia , Trypanosoma cruzi/imunologia , Animais , Atrofia , Linfócitos B/imunologia , Proliferação de Células , Humanos , Linfonodos/imunologia , Depleção Linfocítica , Baço/imunologia , Linfócitos T/imunologia , Timo/imunologia
19.
Immunopharmacol Immunotoxicol ; 31(2): 159-73, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18785049

RESUMO

Caspases are cysteine aspartases acting either as initiators (caspases 8, 9, and 10) or executioners (caspases 3, 6, and 7) to induce programmed cell death by apoptosis. Parasite infections by certain intracellular protozoans increase host cell life span by targeting caspase activation. Conversely, caspase activation, followed by apoptosis of lymphocytes and other cells, prevents effective immune responses to chronic parasite infection. Here we discuss how pharmacological inhibition of caspases might affect the immunity to protozoan infections, by either blocking or delaying apoptosis.


Assuntos
Antiprotozoários/uso terapêutico , Apoptose/efeitos dos fármacos , Inibidores de Caspase , Infecções por Protozoários/tratamento farmacológico , Animais , Antiprotozoários/imunologia , Apoptose/imunologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Camundongos , Infecções por Protozoários/enzimologia , Infecções por Protozoários/imunologia , Receptores de Morte Celular/imunologia
20.
Eur J Immunol ; 38(1): 139-46, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18085669

RESUMO

Infection with Trypanosoma cruzi causes expansion of subcutaneous (SLN) and atrophy of mesenteric (MLN) lymph nodes. Here we show that excision of MLN increased parasitemia in T. cruzi-infected mice. We then studied how apoptosis of MLN cells affects immune responses to infection. T cell apoptosis increased in the MLN compared to SLN in T. cruzi-infected mice. Absolute numbers of naïve T cells decreased, and activated T cells failed to accumulate in MLN during infection. In addition, activated T cells from MLN produced less IL-2, IFN-gamma, IL-4, and IL-10 than T cells from SLN. Treatment with IL-4 or with caspase-9 inhibitor increased the recovery of viable T cells in vitro. Treatment with caspase-9 inhibitor also increased the production of cytokines by MLN T cells from infected mice. Moreover, injection of a pan caspase inhibitor prevented MLN atrophy during T. cruzi infection. Caspase-9, but not caspase-8, inhibitor also reduced MLN atrophy and increased the recovery of naïve and activated T cells from MLN. These findings indicate that caspase-mediated apoptosis and defective cytokine production are implicated in MLN atrophy and affect immune responses to T. cruzi infection.


Assuntos
Apoptose/imunologia , Doença de Chagas/imunologia , Linfonodos/imunologia , Mesentério/imunologia , Pele/imunologia , Linfócitos T/imunologia , Animais , Atrofia , Caspases/efeitos dos fármacos , Caspases/imunologia , Caspases/metabolismo , Citocinas/biossíntese , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Linfonodos/microbiologia , Linfonodos/patologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/microbiologia , Linfócitos T/patologia , Trypanosoma cruzi
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