RESUMO
Disorders of gastrointestinal motility are the major physiologic problem in chagasic megacolon. The contraction mechanism is complex and controlled by different cell types such as enteric neurons, smooth muscle, telocytes, and an important pacemaker of the intestine, the interstitial cells of Cajal (ICCs). The role of ICCs in the progression of acute and chronic Chagas disease remains unclear. In the present work, we investigate the aspects of ICCs in a long-term model of Chagas disease that mimics the pathological aspects of human megacolon. Different subsets of ICCs isolated from Auerbach's myenteric plexuses and muscle layers of control and Trypanosoma cruzi infected animals were determined by analysis of CD117, CD44, and CD34 expression by flow cytometer. Compared with the respective controls, the results showed a reduced frequency of mature ICCs in the acute phase and three months after infection. These results demonstrate for the first time the phenotypic distribution of ICCs associated with functional dysfunction in a murine model of chagasic megacolon. This murine model proved valuable for studying the profile of ICCs as an integrative system in the gut and as a platform for understanding the mechanism of chagasic megacolon development.
Assuntos
Doença de Chagas , Modelos Animais de Doenças , Células Intersticiais de Cajal , Megacolo , Animais , Células Intersticiais de Cajal/patologia , Doença de Chagas/patologia , Doença de Chagas/fisiopatologia , Megacolo/parasitologia , Megacolo/patologia , Megacolo/fisiopatologia , Camundongos , Citometria de Fluxo , Masculino , Trypanosoma cruzi/fisiologiaRESUMO
Current treatments for chronic Chagas cardiomyopathy, a disease with high mortality rates and caused by the protozoan Trypanosoma cruzi, are unsatisfactory. Myocardial inflammation, including endothelial activation, is responsible for the structural and functional damage seen in the chronic phase. The clinical efficacy of benznidazole could be improved by decreasing chronic inflammation. Statins, which have anti-inflammatory properties, may improve the action of benznidazole. Here, the action of simvastatin in a murine model of chronic Chagas cardiomyopathy and the link with the production of the proresolving eicosanoid 15-epi-lipoxin A4, produced by 5-lipoxygenase, are evaluated. Simvastatin decreased the expression of the adhesion molecules E-selectin, intracellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1) in T. cruzi-infected mice. However, when this drug was administered to 5-lipoxygenase-deficient mice, the anti-inflammatory effect was not observed unless exogenous 15-epi-lipoxin A4 was administered. Thus, in chronic Chagas disease, 5-epi-lipoxin A4 induced by simvastatin treatment could improve the pathophysiological condition of patients by increasing the trypanocidal action of benznidazole.
Assuntos
Anticolesterolemiantes/farmacologia , Cardiomiopatia Chagásica/tratamento farmacológico , Nitroimidazóis/farmacologia , Parasitemia/tratamento farmacológico , Sinvastatina/farmacologia , Tripanossomicidas/farmacologia , Animais , Araquidonato 5-Lipoxigenase/deficiência , Araquidonato 5-Lipoxigenase/genética , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/mortalidade , Cardiomiopatia Chagásica/parasitologia , Doença Crônica , Modelos Animais de Doenças , Quimioterapia Combinada , Selectina E/genética , Selectina E/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Endotélio/parasitologia , Regulação da Expressão Gênica , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Lipoxinas/antagonistas & inibidores , Lipoxinas/metabolismo , Lipoxinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Parasitemia/metabolismo , Parasitemia/mortalidade , Parasitemia/parasitologia , Análise de Sobrevida , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/patogenicidade , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
AIM: Leukotrienes (LTs) are pro-inflammatory lipid mediators formed by the enzyme 5-lipoxygenase (5-LO). The involvement of 5-LO metabolites in periodontal disease (PD) is not well defined. This study aimed to assess the role of 5-LO in experimental PD induced by Aggregatibacter actinomycetemcomitans (Aa). MATERIAL AND METHODS: In vivo experiments were carried out using SV129 wild-type (WT) and 5-LO-deficient (5lo-/- ) mice inoculated with Aa. Osteoclasts were stimulated in vitro with AaLPS in the presence or not of selective inhibitors of the 5-LO pathway, or LTB4 or platelet-activating factor (PAF), as PAF has already been shown to increase osteoclast activity. RESULTS: In 5lo-/- mice, there were no loss of alveolar bone and less TRAP-positive osteoclasts in periodontal tissues, after Aa inoculation, despite local production of TNF-α and IL-6. The differentiation and activity of osteoclasts stimulated with AaLPS were diminished in the presence of BLT1 antagonist or 5-LO inhibitor, but not in the presence of cysteinyl leukotriene receptor antagonist. The osteoclast differentiation induced by PAF was impaired by the BLT1 antagonism. CONCLUSION: In conclusion, LTB4 but not CysLTs is important for Aa-induced alveolar bone loss. Overall, LTB4 affects osteoclast differentiation and activity and is a key intermediate of PAF-induced osteoclastogenesis.
Assuntos
Aggregatibacter actinomycetemcomitans/patogenicidade , Perda do Osso Alveolar/enzimologia , Perda do Osso Alveolar/microbiologia , Araquidonato 5-Lipoxigenase/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Hidroxiureia/análogos & derivados , Hidroxiureia/farmacologia , Interleucina-6/metabolismo , Camundongos , Osteoclastos/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection. The relevance of AhR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with T. cruzi (Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO(-)) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart. In vitro, AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental T. cruzi infection.
Assuntos
Doença de Chagas/fisiopatologia , Citocinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/fisiologia , Trypanosoma cruzi/fisiologia , Animais , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Doença de Chagas/metabolismo , Doença de Chagas/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Miocardite/metabolismo , Miocardite/patologia , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Baço/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
Malaria is considered a neglected disease and public health problem, affecting >200 million people worldwide. In the present study we used the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria (CM) in C57BL/6 mice. After rescue from CM and parasite clearance, animals were submitted to a seizure susceptibility test (45 days after infection) using a low dose of pentylenetetrazol (PTZ, 30 mg/kg) and monitored with use of behavioral and electroencephalography (EEG) methods. Mice rescued from CM presented a reduced latency to myoclonic and tonic-clonic seizures and an increased duration of tonic-clonic seizures. In addition, quantitative analysis of EEG revealed a decrease in relative power at beta frequency band in PbA-infected animals after PTZ injection. Our results suggest that CM may lead to increased susceptibility to seizures in mice.
Assuntos
Convulsivantes/efeitos adversos , Suscetibilidade a Doenças/induzido quimicamente , Epilepsia/induzido quimicamente , Pentilenotetrazol/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Malária Cerebral/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/patogenicidade , Estatísticas não Paramétricas , Fatores de TempoRESUMO
PURPOSE OF REVIEW: American trypanosomiasis, or Chagas disease, is a lifelong and persistent infection caused by the protozoan Trypanosoma cruzi and is the most significant cause of morbidity and mortality in South and Central America. Owing to immigration and additional risks from blood transfusion and organ transplantation, the number of reported cases of Chagas disease has increased recently in Europe and the USA. The disease is caused by a moderate to intense lasting inflammatory response that triggers local expression of inflammatory mediators and activates and recruits leukocytes to various tissues to eliminate the parasites. RECENT FINDINGS: This long-term inflammatory process triggers biochemical, physiological and morphological alterations and clinical changes in the digestive, nervous and cardiac (e.g. myocarditis, arrhythmias, congestive heart failure, autonomic dysfunctions and microcirculatory disturbances) systems. Indeed, the pathogenesis of Chagas disease is intricate and multifactorial, and the roles of the parasite and the immune response in initiating and maintaining the disease are still controversial. SUMMARY: In this review, we discuss the current knowledge of 'strategies' employed by the parasite to persist in the host and host defence mechanisms against Trypanosoma cruzi infection, which can result in equilibrium (absence of the disease) or disease development, mainly in the cardiac systems.
Assuntos
Doença de Chagas/fisiopatologia , Inflamação/parasitologia , Miocárdio/patologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/genética , Anticorpos Antiprotozoários/sangue , Autoimunidade , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Coração/parasitologia , Interações Hospedeiro-Parasita , Humanos , Trypanosoma cruzi/isolamento & purificaçãoRESUMO
BACKGROUND: Cerebral malaria (CM) is debilitating and sometimes fatal. Disease severity has been associated with poor treatment access, therapeutic complexity and drug resistance and, thus, alternative therapies are increasingly necessary. In this study, the effect of the administration of Agaricus blazei, a mushroom of Brazilian origin in a model of CM caused by Plasmodium berghei, strain ANKA, was investigated in mice. METHODS: C57BL/6 mice were pre-treated with aqueous extract or fractions of A. blazei, or chloroquine, infected with P. berghei ANKA and then followed by daily administration of A. blazei or chloroquine. Parasitaemia, body weight, survival and clinical signs of the disease were evaluated periodically. The concentration of pro-and anti-inflammatory cytokines, histopathology and in vitro analyses were performed. RESULTS: Mice treated with A. blazei aqueous extract or fraction C, that shows antioxidant activity, displayed lower parasitaemia, increased survival, reduced weight loss and protection against the development of CM. The administration of A. blazei resulted in reduced levels of TNF, IL-1ß and IL-6 production when compared to untreated P. berghei-infected mice. Agaricus blazei (aqueous extract or fraction C) treated infected mice displayed reduction of brain lesions. Although chloroquine treatment reduced parasitaemia, there was increased production of proinflammatory cytokines and damage in the CNS not observed with A. blazei treatment. Moreover, the in vitro pretreatment of infected erythrocytes followed by in vivo infection resulted in lower parasitaemia, increased survival, and little evidence of clinical signs of disease. CONCLUSIONS: This study strongly suggests that the administration of A. blazei (aqueous extract or fraction C) was effective in improving the consequences of CM in mice and may provide novel therapeutic strategies.
Assuntos
Agaricus/química , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Produtos Biológicos/farmacologia , Malária Cerebral/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antimaláricos/química , Antimaláricos/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Citocinas/sangue , Feminino , Malária Cerebral/fisiopatologia , Malária Cerebral/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Infectious diseases are the second leading cause of death worldwide. Noninvasive small-animal imaging has become an important research tool for preclinical studies of infectious diseases. Imaging studies permit enhanced information through longitudinal studies of the same animal during the infection. Herein, we briefly review recent studies of animal models of infectious disease that have used imaging modalities.
Assuntos
Doenças Transmissíveis/diagnóstico , Diagnóstico por Imagem/métodos , Modelos Animais de Doenças , AnimaisRESUMO
Chagas disease, caused by Trypanosoma cruzi, is an important cause of morbidity and mortality primarily resulting from cardiac dysfunction, although T. cruzi infection results in inflammation and cell destruction in many organs. We found that T. cruzi (Brazil strain) infection of mice results in pancreatic inflammation and parasitism within pancreatic ß-cells with apparent sparing of α cells and leads to the disruption of pancreatic islet architecture, ß-cell dysfunction, and surprisingly, hypoglycemia. Blood glucose and insulin levels were reduced in infected mice during acute infection and insulin levels remained low into the chronic phase. In response to the hypoglycemia, glucagon levels 30 days postinfection were elevated, indicating normal α-cell function. Administration of L-arginine and a ß-adrenergic receptor agonist (CL316, 243, respectively) resulted in a diminished insulin response during the acute and chronic phases. Insulin granules were docked, but the lack of insulin secretion suggested an inability of granules to fuse at the plasma membrane of pancreatic ß-cells. In the liver, there was a concomitant reduced expression of glucose-6-phosphatase mRNA and glucose production from pyruvate (pyruvate tolerance test), demonstrating defective hepatic gluconeogenesis as a cause for the T. cruzi-induced hypoglycemia, despite reduced insulin, but elevated glucagon levels. The data establishes a complex, multi-tissue relationship between T. cruzi infection, Chagas disease, and host glucose homeostasis.
Assuntos
Doença de Chagas/metabolismo , Glucose/metabolismo , Homeostase , Tecido Adiposo Branco/patologia , Animais , Glicemia/metabolismo , Doença de Chagas/sangue , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Modelos Animais de Doenças , Imunofluorescência , Glucagon/sangue , Gluconeogênese , Insulina/sangue , Fígado/metabolismo , Fígado/parasitologia , Fígado/patologia , Masculino , Camundongos , Pâncreas/parasitologia , Pâncreas/patologia , Pâncreas/ultraestrutura , Trypanosoma cruzi/fisiologiaRESUMO
The protozoan parasite Trypanosoma cruzi causes Chagas disease. Cardiac and adipose tissues are among the early targets of infection and are sites of persistent infection. In the heart and adipose tissue, T. cruzi infection results in an upregulation of pro-inflammatory mediators. In the heart, infection is associated with an increase in the markers of oxidative stress. To date, markers of oxidative stress have not been evaluated in adipose tissue in this infection. Brown and white adipose tissues were obtained from CD-1 mice infected with the Brazil strain of T. cruzi for 15, 30, and 130 days post infection. Protein carbonylation and lipid peroxidation assays were performed on these samples. There was an upregulation of these markers of oxidative stress at all time-points in both white and brown adipose tissue. Determinants of anti-oxidative stress were downregulated at similar time-points. This increase in oxidative stress during T. cruzi infection most likely has a deleterious effect on host metabolism and on the heart.
Assuntos
Tecido Adiposo/metabolismo , Doença de Chagas/metabolismo , Estresse Oxidativo/fisiologia , Trypanosoma cruzi , Animais , Biomarcadores , Doença de Chagas/parasitologia , Regulação da Expressão Gênica , Masculino , CamundongosRESUMO
Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol (DAG) kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting DAG to phosphatidic acid (PA). We demonstrate that the zeta isoform of the DGK family (DGKzeta) is expressed in macrophages (Mphi) and dendritic cells. DGKzeta deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor alpha production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKzeta negatively controls the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and that inhibition of PI3K activity or treatment with PA can restore lipopolysaccharide-induced IL-12 production by DGKzeta-deficient Mphi. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKzeta promotes TLR responses via a pathway involving inhibition of PI3K.
Assuntos
Diacilglicerol Quinase/metabolismo , Toxoplasma/imunologia , Toxoplasmose/enzimologia , Toxoplasmose/imunologia , Animais , Células Cultivadas , Células Dendríticas/enzimologia , Diacilglicerol Quinase/deficiência , Diacilglicerol Quinase/genética , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Proteínas I-kappa B/metabolismo , Interleucina-12/biossíntese , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Camundongos , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Ácidos Fosfatídicos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Células Th1/enzimologia , Células Th1/imunologia , Células Th1/parasitologia , Receptores Toll-Like/metabolismo , Toxoplasmose/parasitologia , Toxoplasmose/patologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Infection with Trypanosoma cruzi induces inflammation, which limits parasite proliferation but may result in chagasic heart disease. Suppressor of cytokine signaling 2 (SOCS2) is a regulator of immune responses and may therefore participate in the pathogenesis of T. cruzi infection. SOCS2 is expressed during T. cruzi infection, and its expression is partially reduced in infected 5-lipoxygenase-deficient [knockout (KO)] mice. In SOCS2 KO mice, there was a reduction in both parasitemia and the expression of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-10, SOCS1, and SOCS3 in the spleen. Expression of IFN-γ, TNF-α, SOCS1, and SOCS3 was also reduced in the hearts of infected SOCS2 KO mice. There was an increase in the generation and expansion of T regulatory (Treg) cells and a decrease in the number of memory cells in T. cruzi-infected SOCS2 KO mice. Levels of lipoxinA(4) (LXA(4)) increased in these mice. Echocardiography studies demonstrated an impairment of cardiac function in T. cruzi-infected SOCS2 KO mice. There were also changes in calcium handling and in action potential waveforms, and reduced outward potassium currents in isolated cardiac myocytes. Our data suggest that reductions of inflammation and parasitemia in infected SOCS2-deficient mice may be secondary to the increases in Treg cells and LXA(4) levels. This occurs at the cost of greater infection-associated heart dysfunction, highlighting the relevance of balanced inflammatory and immune responses in preventing severe T. cruzi-induced disease.
Assuntos
Cardiomiopatia Chagásica/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Doença Aguda , Animais , Araquidonato 5-Lipoxigenase/fisiologia , Células Cultivadas , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/fisiopatologia , Citocinas/biossíntese , Modelos Animais de Doenças , Coração/parasitologia , Lipoxinas/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/imunologia , Carga Parasitária , Parasitemia/imunologia , Técnicas de Patch-Clamp , Proteínas Supressoras da Sinalização de Citocina/deficiência , Subpopulações de Linfócitos T/imunologia , Trypanosoma cruzi/isolamento & purificaçãoRESUMO
Trypanosoma cruzi infection leads to development of chronic Chagas disease. In this article, we provide an update on the current knowledge of the mechanisms employed by the parasite to gain entry into the host cells and establish persistent infection despite activation of a potent immune response by the host. Recent studies point to a number of T. cruzi molecules that interact with host cell receptors to promote parasite invasion of the diverse host cells. T. cruzi expresses an antioxidant system and thromboxane A(2) to evade phagosomal oxidative assault and suppress the host's ability to clear parasites. Additional studies suggest that besides cardiac and smooth muscle cells that are the major target of T. cruzi infection, adipocytes and adipose tissue serve as reservoirs from where T. cruzi can recrudesce and cause disease decades later. Further, T. cruzi employs at least four strategies to maintain a symbiotic-like relationship with the host, and ensure consistent supply of nutrients for its own survival and long-term persistence. Ongoing and future research will continue to help refining the models of T. cruzi invasion and persistence in diverse tissues and organs in the host.
Assuntos
Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Interações Hospedeiro-Patógeno , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/patogenicidade , Animais , Doença Crônica , Humanos , Evasão da Resposta Imune , Modelos BiológicosRESUMO
BACKGROUND: Cerebral malaria (CM) is a clinical syndrome resulting from Plasmodium falciparum infection. A wide range of clinical manifestations follow the disease including cognitive dysfunction, seizures and coma. CM pathogenesis remains incompletely understood and without treatment this condition is invariably fatal. Artesunate has been accepted as the most effective drug for treating severe malaria. Besides its antiparasitic activity, an anti-inflammatory property has also been reported. In the current study, the immunomodulatory role of artesunate was investigated using a Plasmodium berghei ANKA model of CM, trough evaluation of behavioural changes and cytokines expression in hippocampus and in frontal cortex. METHODS: C57Bl/6 mice were infected with P. berghei by intraperitoneal route, using a standardized inoculation of 106 parasitized erythrocytes. Memory function was evaluated using the step-down inhibitory avoidance test. The mRNA expression of IFN-γ, IL-1ß, IL-6 and TNF in the frontal cortex and hippocampus of control and infected mice on day 5 post-infection were estimated by quantitative real time PCR. Plasmodium berghei -infected mice also received intraperitoneally a single dose of artesunate (32 mg/kg) on day 4 post-infection, and 24 hours after treatment behavioural and immunological analysis were performed. The protein levels of cytokines IL-2, IL-6, IL-10, IL-17, IFN-γ, TNF in the serum, frontal cortex and hippocampus of controls and P. berghei -infected mice treated or not treated with artesunate were determined using a cytometric bead array (CBA) kit. The survival and neurological symptoms of CM were also registered. RESULTS: CM mice presented a significant impairment of aversive memory compared to controls on day 5 post-infection. A higher mRNA expression of pro-inflammatory cytokines was found in the hippocampus and frontal cortex of infected mice. A single dose of artesunate was also able to decrease the expression of inflammatory cytokines in the hippocampus and frontal cortex of P. berghei-infected mice. In parallel, a significant improvement in neurological symptoms and survival were observed in artesunate treated mice. CONCLUSIONS: In summary, the current study provided further evidence that CM affects key brain areas related to cognition process. In addition, different patterns of cytokine expression during the course of CM could be modulated by a single administration of the anti-malarial artesunate.
Assuntos
Anti-Inflamatórios/administração & dosagem , Artemisininas/administração & dosagem , Malária Cerebral/tratamento farmacológico , Malária Cerebral/patologia , Animais , Antimaláricos/administração & dosagem , Artesunato , Citocinas/biossíntese , Citocinas/sangue , Citocinas/genética , Técnicas Citológicas , Modelos Animais de Doenças , Feminino , Lobo Frontal/patologia , Perfilação da Expressão Gênica , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de SobrevidaRESUMO
Control of inflammation is crucial to prevent damage to the host during infection. Lipoxins and aspirin-triggered lipoxins are crucial modulators of proinflammatory responses; however, their intracellular mechanisms have not been completely elucidated. We previously showed that lipoxin A4 (LXA4) controls migration of dendritic cells (DCs) and production of interleukin (IL)-12 in vivo. In the absence of LXA4 biosynthetic pathways, the resulting uncontrolled inflammation during infection is lethal, despite pathogen clearance. Here we show that lipoxins activate two receptors in DCs, AhR and LXAR, and that this activation triggers expression of suppressor of cytokine signaling (SOCS)-2. SOCS-2-deficient DCs are hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of LXA4, but not to IL-10. Upon infection with an intracellular pathogen, SOCS-2-deficient mice had uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte infiltration and elevated mortality. We also show that SOCS-2 is a crucial intracellular mediator of the anti-inflammatory actions of aspirin-induced lipoxins in vivo.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Lipoxinas/farmacologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Encéfalo/citologia , Encéfalo/parasitologia , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-12/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Proteínas Supressoras da Sinalização de Citocina/deficiência , Proteínas Supressoras da Sinalização de Citocina/genética , Toxoplasma/patogenicidadeRESUMO
Trypanosoma cruzi infection in humans and experimental animals causes Chagas disease which is often accompanied by myocarditis, cardiomyopathy, and vasculopathy. T. cruzi-derived thromboxane A2 (TXA2) modulates vasculopathy and other pathophysiological features of Chagasic cardiomyopathy. Here, we provide evidence that epimastigotes, trypomastigotes, and amastigotes of T. cruzi (Brazil and Tulahuen strains) express a biologically active prostanoid receptor (PR) that is responsive to TXA2 mimetics, e.g. IBOP. This putative receptor, TcPR, is mainly localized in the flagellar membrane of the parasites and shows a similar glycosylation pattern to that of bona fide thromboxane prostanoid (TP) receptors obtained from human platelets. Furthermore, TXA2-PR signal transduction activates T. cruzi-specific MAPK pathways. While mammalian TP is a G-protein coupled receptor (GPCR); T. cruzi genome sequencing has not demonstrated any confirmed GPCRs in these parasites. Based on this genome sequencing it is likely that TcPR is unique in these protists with no counterpart in mammals. TXA2 is a potent vasoconstrictor which contributes to the pathogenesis of Chagasic cardiovascular disease. It may, however, also control parasite differentiation and proliferation in the infected host allowing the infection to progress to a chronic state.
Assuntos
Prostaglandinas/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Membrana Celular/química , Flagelos/química , Glicosilação , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Tromboxano A2/análogos & derivados , Tromboxano A2/metabolismo , Trypanosoma cruzi/químicaRESUMO
Trypanosoma cruzi infects all nucleated cells in both humans and experimental animals. As a prelude to our studies of T. cruzi pathogenesis in the gastrointestinal system, we have initiated in vitro cultures of gut (Caco-2 and HT-29) and pancreatic (Panc-1) epithelial cells. We show that along with primary human fibroblasts, all three cell lines are susceptible to infection and support proliferation of T. cruzi. Infection with T. cruzi modified dramatically the cytokines elaborated by these cells. Substantially greater quantities of IL-5 and TGF-ß1 were produced by fibroblasts and Caco-2 and Panc-1 cells, whereas secretion of IFN-γ and TNF-α was greatly reduced in all three cell types. Since these cells are not known to be the primary sources of IFN-γ, we examined IFN-γ mRNA expression in these cells. Both Caco-2 and Panc-1 cells were found to express IFN-γ mRNA, validating its secretion. These findings may provide insight into signaling pathways that mediate innate immunity to T. cruzi and pathogenesis of gastrointestinal and pancreatic alterations in Chagas disease.
Assuntos
Doença de Chagas/imunologia , Citocinas/imunologia , Células Epiteliais/imunologia , Trypanosoma cruzi/patogenicidade , Células CACO-2 , Linhagem Celular , Colo/citologia , Células Epiteliais/parasitologia , Fibroblastos/imunologia , Fibroblastos/parasitologia , Humanos , Imunidade Inata , Interferon gama/imunologia , Interleucina-5/imunologia , Pâncreas/citologia , Trypanosoma cruzi/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Brown adipose tissue (BAT) and white adipose tissue (WAT) and adipocytes are targets of Trypanosoma cruzi infection. Adipose tissue obtained from CD-1 mice 15 days after infection, an early stage of infection revealed a high parasite load. There was a significant increase in macrophages in infected adipose tissue and a reduction in lipid accumulation, adipocyte size, and fat mass and increased expression of lipolytic enzymes. Infection increased levels of Toll-like receptor (TLR) 4 and TLR9 and in the expression of components of the mitogen-activated protein kinase pathway. Protein and messenger RNA (mRNA) levels of peroxisome proliferator-activated receptor γ were increased in WAT, whereas protein and mRNA levels of adiponectin were significantly reduced in BAT and WAT. The mRNA levels of cytokines, chemokines, and their receptors were increased. Nuclear Factor Kappa B levels were increased in BAT, whereas Iκκ-γ levels increased in WAT. Adipose tissue is an early target of T. cruzi infection.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Doença de Chagas/parasitologia , RNA Mensageiro/metabolismo , Transdução de Sinais , Trypanosoma cruzi , Adipócitos/parasitologia , Adipócitos/patologia , Adiponectina/metabolismo , Tecido Adiposo Marrom/parasitologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/parasitologia , Tecido Adiposo Branco/patologia , Animais , Doença de Chagas/patologia , Quimiocinas/metabolismo , Citocinas , Quinase I-kappa B/metabolismo , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , PPAR gama/metabolismo , Receptores de Quimiocinas/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismoRESUMO
The role of caveolin and caveolae in the pathogenesis of infection has only recently been appreciated. In this chapter, we have highlighted some important new data on the role of caveolin in infections due to bacteria, viruses and fungi but with particular emphasis on the protozoan parasites Leishmania spp., Trypanosoma cruzi and Toxoplasma gondii. This is a continuing area of research and the final chapter has not been written on this topic.