RESUMO
Cerebral malaria (CM) is a neurological complication derived from the Plasmodium falciparum infection in humans. The mechanisms involved in the disease progression are still not fully understood, but both the sequestration of infected red blood cells (iRBC) and leukocytes and an exacerbated host inflammatory immune response are significant factors. In this study, we investigated the effect of Monocyte Locomotion Inhibitory Factor (MLIF), an anti-inflammatory peptide, in a well-characterized murine model of CM. Our data showed that the administration of MLIF increased the survival and avoided the neurological signs of CM in Plasmodium berghei ANKA (PbA) infected C57BL/6 mice. MLIF administration down-regulated systemic inflammatory mediators such as IFN-γ, TNF-α, IL-6, CXCL2, and CCL2, as well as the in situ expression of TNF-α in the brain. In the same way, MLIF reduced the expression of CD31, CD36, CD54, and CD106 in the cerebral endothelium of infected animals and prevented the sequestration of iRBC and leucocytes in the brain microvasculature. Furthermore, MLIF inhibited the activation of astrocytes and microglia and preserved the integrity of the blood-brain barrier (BBB). In conclusion, our results demonstrated that the administration of MLIF increased survival and conferred neuroprotection by decreasing neuroinflammation in murine CM.
Assuntos
Anti-Inflamatórios/administração & dosagem , Malária Cerebral/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Oligopeptídeos/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Feminino , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Malária Cerebral/imunologia , Malária Cerebral/parasitologia , Malária Cerebral/patologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Plasmodium berghei/imunologiaRESUMO
Malaria is an infectious disease of major worldwide clinical importance that causes a variety of severe, or complicated, syndromes including cerebral malaria, which is often fatal. Leukocyte integrins are essential for host defense but also mediate physiologic responses of the innate and adaptive immune systems. We previously showed that targeted deletion of the αD subunit (αD-/-) of the αDß2 integrin, which is expressed on key leukocyte subsets in mice and humans, leads to absent expression of the integrin heterodimer on murine macrophages and reduces mortality in mice infected with Plasmodium berghei ANKA (P. berghei ANKA). To further identify mechanisms involved in the protective effect of αD deletion in this model of severe malaria we examined wild type C57BL/6 (WT) and αD-/- mice after P. berghei ANKA infection and found that vessel plugging and leukocyte infiltration were significantly decreased in the brains of αD-/- animals. Intravital microscopy demonstrated decreased rolling and adhesion of leukocytes in cerebral vessels of αD-/- mice. Flow cytometry analysis showed decreased T-lymphocyte accumulation in the brains of infected αD-/- animals. Evans blue dye exclusion assays demonstrated significantly less dye extravasation in the brains of αD-/- mice, indicating preserved blood-brain barrier integrity. WT mice that were salvaged from P. berghei ANKA infection by treatment with chloroquine had impaired aversive memory, which was not observed in αD-/- mice. We conclude that deletion of integrin αDß2 alters the natural course of experimental severe malaria, demonstrating previously unrecognized activities of a key leukocyte integrin in immune-inflammatory responses that mediate cerebral involvement.
Assuntos
Antígenos CD11/metabolismo , Cadeias alfa de Integrinas/metabolismo , Malária/fisiopatologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Antígenos CD11/fisiologia , Cloroquina/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Cadeias alfa de Integrinas/fisiologia , Integrinas/imunologia , Integrinas/metabolismo , Contagem de Leucócitos , Leucócitos/metabolismo , Leucócitos/fisiologia , Macrófagos/metabolismo , Malária/genética , Malária Cerebral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium berghei/metabolismoRESUMO
Dendritic cells have an important role in immune surveillance. After being exposed to microbial components, they migrate to secondary lymphoid organs and activate T lymphocytes. Here we show that during mouse malaria, splenic inflammatory monocytes differentiate into monocyte-derived dendritic cells (MO-DCs), which are CD11b+F4/80+CD11c+MHCIIhighDC-SIGNhighLy6c+ and express high levels of CCR5, CXCL9 and CXCL10 (CCR5+CXCL9/10+ MO-DCs). We propose that malaria-induced splenic MO-DCs take a reverse migratory route. After differentiation in the spleen, CCR5+CXCL9/10+ MO-DCs traffic to the brain in a CCR2-independent, CCR5-dependent manner, where they amplify the influx of CD8+ T lymphocytes, leading to a lethal neuropathological syndrome.
Assuntos
Encéfalo/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/fisiologia , Malária Cerebral/imunologia , Baço/fisiologia , Animais , Antígenos de Protozoários/imunologia , Encéfalo/citologia , Encéfalo/patologia , Diferenciação Celular/imunologia , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Modelos Animais de Doenças , Humanos , Malária Cerebral/parasitologia , Malária Cerebral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Plasmodium berghei/imunologia , Receptores CCR5/metabolismo , Baço/citologiaRESUMO
Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2(-/-)) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-ß, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2(-/-) mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-ß in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2(-/-) mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2(-/-) mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2(-/-) mice to the background levels observed in infected WT, with remarkable exception of increased CD8(+)IFN(+) T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection.
Assuntos
Malária Cerebral/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Malária Cerebral/metabolismo , Malária Cerebral/parasitologia , Malária Cerebral/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Crescimento Neural/metabolismo , Plasmodium berghei/isolamento & purificação , Baço/metabolismo , Proteínas Supressoras da Sinalização de Citocina/antagonistas & inibidores , Proteínas Supressoras da Sinalização de Citocina/deficiência , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Experimental cerebral malaria (ECM) is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. Phosphatidylinositol 3-kinase γ (PI3Kγ) is central in signaling diverse cellular functions. Using PI3Kγ-deficient mice (PI3Kγ-/-) and a specific PI3Kγ inhibitor, we investigated the relevance of PI3Kγ for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA) infection. Infected PI3Kγ-/- mice had greater survival despite similar parasitemia levels in comparison with infected wild type mice. Histopathological analysis demonstrated reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Kγ-/- mice. PI3Kγ deficiency also presented lower microglial activation (Iba-1+ reactive microglia) and T cell cytotoxicity (Granzyme B expression) in the brain. Additionally, on day 6 post-infection, CD3+CD8+ T cells were significantly reduced in the brain of infected PI3Kγ-/- mice when compared to infected wild type mice. Furthermore, expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkB-α in the whole brain were also markedly lower in infected PI3Kγ-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Kγ inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Kγ in the pathogenesis of ECM.
Assuntos
Classe Ib de Fosfatidilinositol 3-Quinase/genética , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Malária Cerebral/imunologia , Malária Cerebral/patologia , Plasmodium berghei/imunologia , Animais , Encéfalo/imunologia , Modelos Animais de Doenças , Matriz Extracelular/imunologia , Matriz Extracelular/parasitologia , Feminino , Humanos , Pulmão/enzimologia , Pulmão/parasitologia , Malária Cerebral/enzimologia , Malária Cerebral/parasitologia , Camundongos , Inibidores de Fosfoinositídeo-3 Quinase , Quinoxalinas/farmacologia , Análise de Sobrevida , Tiazolidinedionas/farmacologiaRESUMO
The contribution of T cells in severe malaria pathogenesis has been described. Here, we provide evidence for the potential role of angiotensin II (Ang II) in modulating splenic T cell responses in a rodent model of cerebral malaria. T cell activation induced by infection, determined by 3 to 4-fold enhancement in CD69 expression, was reduced to control levels when mice were treated with 20 mg/kg losartan (IC50â=â0.966 mg/kg/d), an AT1 receptor antagonist, or captopril (IC50â=â1.940 mg/kg/d), an inhibitor of angiotensin-converting enzyme (ACE). Moreover, the production of interferon-γ and interleukin-17 by CD4+ T cells diminished 67% and 70%, respectively, by both treatments. Losartan reduced perforin expression in CD8+ T cells by 33% while captopril completely blocked it. The upregulation in chemokine receptor expression (CCR2 and CCR5) observed during infection was abolished and CD11a expression was partially reduced when mice were treated with drugs. T cells activated by Plasmodium berghei ANKA antigens showed 6-fold enhance in AT1 levels in comparison with naive cells. The upregulation of AT1 expression was reduced by losartan (80%) but not by captopril. Our results suggest that the AT1/Ang II axis has a role in the establishment of an efficient T cell response in the spleen and therefore could participate in a misbalanced parasite-induced T cell immune response during P. berghei ANKA infection.
Assuntos
Angiotensina II/metabolismo , Malária/imunologia , Malária/metabolismo , Plasmodium berghei/imunologia , Baço/imunologia , Subpopulações de Linfócitos T/imunologia , Angiotensina II/imunologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Adesão Celular/imunologia , Linhagem Celular , Movimento Celular/imunologia , Citocinas/biossíntese , Citocinas/sangue , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Malária Cerebral/imunologia , Camundongos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismoRESUMO
Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Mediadores da Inflamação/uso terapêutico , Lovastatina/uso terapêutico , Malária Cerebral/tratamento farmacológico , Animais , Encéfalo/imunologia , Antígeno CD11b/efeitos dos fármacos , Antígeno CD11b/genética , Quimiocinas/sangue , Cloroquina/uso terapêutico , Transtornos Cognitivos/complicações , Transtornos Cognitivos/parasitologia , Citocinas/sangue , Edema/tratamento farmacológico , Endotélio/efeitos dos fármacos , Endotélio/imunologia , Endotélio/parasitologia , Heme Oxigenase-1/efeitos dos fármacos , Heme Oxigenase-1/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/tratamento farmacológico , Mediadores da Inflamação/farmacologia , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Leucócitos/parasitologia , Malária Cerebral/imunologia , Malária Cerebral/parasitologia , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/imunologia , RNA Mensageiro/efeitos dos fármacosRESUMO
Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection. The underlying mechanisms of CM pathogenesis remain incompletely understood. The imbalance between the release of proinflammatory and anti-inflammatory cytokines has been associated with central nervous system dysfunction found in human and experimental CM. The current study investigated anxiety-like behavior, histopathological changes and release of brain cytokines in C57BL/6 mice infected with Plasmodium berghei strain ANKA (PbA). Anxiety-like behavior was assessed in control and PbA-infected mice using the elevated plus maze test. Histopathological changes in brain tissue were assessed by haematoxylin and eosin staining. Brain concentration of the cytokines IL-1ß, IL-4, IL-10, TNF-α and IFN-γ was determined by ELISA. We found that PbA-infected mice on day 5 post-infection presented anxiety symptoms, histopathological alterations in the brainstem, cerebrum and hippocampus and increased cerebral levels of proinflammatory cytokines IL-1ß and TNF-α. These findings suggest an involvement of central nervous system inflammatory mediators in anxiety symptoms found in CM.
Assuntos
Ansiedade/fisiopatologia , Ansiedade/parasitologia , Encéfalo/fisiopatologia , Citocinas/biossíntese , Malária Cerebral/fisiopatologia , Animais , Ansiedade/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Inflamação/parasitologia , Inflamação/patologia , Inflamação/fisiopatologia , Malária Cerebral/imunologia , Malária Cerebral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/imunologiaRESUMO
Malaria is an important problem of public health. It is estimated that 350 to 500 million clinical cases occur annually, which cause 1.1 and 1.3 million deaths every year. The excessive activation of the immune system plays an important role in the pathogenesis of the disease. The cells of the immune system of Plasmodium-infected individuals not only produce large amounts of cytokines, which have anti-parasite effects, but also participate in the pathogenesis of the severe complications of malaria. A central feature of P. falciparum infection is the sequestration of parasitized erythrocytes within the small vessels of major organs. This involves molecular interactions between antigens of parasitized erythrocytes and host receptors, expressed on the surface of endothelial cells. The increased production of pro-inflammatory cytokines and nitric oxide, followed by the up regulation of endothelial cell adhesion molecules, influences the progression of cerebral lesions. The association of drugs capable of modulating the immune response to anti plasmodial drugs has been evaluated. Antibodies to tumor necrosis factor, pentoxifylline, and thalidomide have been tried for this purpose with variable success. This review submitted this subject to a critical assessment and suggests ways to take advantage of immunomodulatory drugs, associated to anti parasite therapy, to reduce the morbimortality of malaria.
Assuntos
Fatores Imunológicos/uso terapêutico , Malária Cerebral/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Adulto , Animais , Antimaláricos/uso terapêutico , Criança , Quimioterapia Combinada , Humanos , Malária Cerebral/imunologia , Malária Cerebral/fisiopatologia , Malária Falciparum/imunologia , Malária Falciparum/fisiopatologia , Camundongos , Plasmodium falciparum/efeitos dos fármacos , Índice de Gravidade de DoençaRESUMO
Immune responses to malaria infections are characterized by strong T and B cell activation, which, in addition of potentially causing immunopathology, are of poor efficacy against the infection. It is possible that the thymus is involved in the origin of immunopathological reactions and a target during malaria infections. This work was developed in an attempt to further clarify these points. We studied the sequential changes in the thymus of CBA mice infected with Plasmodium berghei ANKA, a model in which 60-90% of the infected animals develop cerebral malaria. During the acute phase of infection, different degrees of thymocyte apoptosis were recorded. (1) starry-sky pattern of diffuse apoptosis with maintenance of cortical-medullary structure; (2) intense apoptosis with cortical atrophy, with absence of large cells; (3) severe cortical thymocyte depletion, resulting in cortical-medullary inversion. In the latter, only residual clusters of small thymocytes were observed within the framework of epithelial cells. The intensity of thymus alterations could not be associated with the degree of parasitemia, the expression of clinical signs of cerebral malaria or intensity of brain lesions. The implications of these events for malaria immunity and pathology are discussed.
Assuntos
Apoptose/imunologia , Malária Cerebral/imunologia , Plasmodium berghei/fisiologia , Timo/imunologia , Animais , Modelos Animais de Doenças , Feminino , Depleção Linfocítica , Malária Cerebral/parasitologia , Malária Cerebral/patologia , Camundongos , Camundongos Endogâmicos CBA , Parasitemia , Índice de Gravidade de Doença , Timo/patologia , Fatores de TempoRESUMO
Immune responses to malaria infections are characterized by strong T and B cell activation, which, in addition of potentially causing immunopathology, are of poor efficacy against the infection. It is possible that the thymus is involved in the origin of immunopathological reactions and a target during malaria infections. This work was developed in an attempt to further clarify these points. We studied the sequential changes in the thymus of CBA mice infected with Plasmodium berghei ANKA, a model in which 60-90 percent of the infected animals develop cerebral malaria. During the acute phase of infection, different degrees of thymocyte apoptosis were recorded: (1) starry-sky pattern of diffuse apoptosis with maintenance of cortical-medullary structure; (2) intense apoptosis with cortical atrophy, with absence of large cells; (3) severe cortical thymocyte depletion, resulting in cortical-medullary inversion. In the latter, only residual clusters of small thymocytes were observed within the framework of epithelial cells. The intensity of thymus alterations could not be associated with the degree of parasitemia, the expression of clinical signs of cerebral malaria or intensity of brain lesions. The implications of these events for malaria immunity and pathology are discussed.
Assuntos
Animais , Feminino , Camundongos , Apoptose/imunologia , Malária Cerebral/imunologia , Malária Cerebral/parasitologia , Plasmodium berghei/fisiologia , Timo/imunologia , Modelos Animais de Doenças , Depleção Linfocítica , Camundongos Endogâmicos CBA , Malária Cerebral/patologia , Parasitemia , Índice de Gravidade de Doença , Fatores de Tempo , Timo/patologiaRESUMO
OBJECTIVE: The effect of castration and subsequent replacement of dehydroepiandrosterone (DHEA) or estradiol on parasitemia, mortality and incidence of cerebral malaria (CM) was evaluated in CBA mice infected with Plasmodium berghei ANKA. METHODS: Female mice were castrated, and groups of 12-15 animals received daily injections of DHEA, estradiol or saline. Four days after the start of treatment, mice were inoculated with 1 x 10(6)P. berghei ANKA-parasitized erythrocytes. DHEA treatment was continued during the 5 days after infection, and estradiol was administered during the follow-up. Parasitemia was evaluated daily in Giemsa-stained blood smears. Signs of CM were determined by the manifestation of coma, limb paralysis and/or convulsions. Plasma TNF-alpha levels were evaluated by sandwich ELISA. Nitric oxide synthase (NOS) activity in the brain of moribund mice was measured by the method of Bredt and Snyder. RESULTS: In non-castrated infected mice, the incidence of CM was 50%, and plasma TNF-alpha increased and brain NOS activity decreased compared to non-infected controls. Castration had no major effect on the parameters analyzed (parasitemia, mortality, CM incidence, TNF-alpha levels or NOS activity). Estradiol replacement caused a decrease in parasitemia but resulted in higher CM incidence and faster mortality, with an increase in NOS activity. CONCLUSIONS: Estradiol modulated the immune response of P. berghei ANKA-infected CBA mice, decreasing parasitemia and increasing NOS activity, and impacted negatively on survival and CM incidence, showing that neuroimmunoendocrine interactions are important in the physiopathogenesis of malaria infections.
Assuntos
Estradiol/fisiologia , Imunidade Inata/imunologia , Malária Cerebral/imunologia , Neuroimunomodulação/imunologia , Parasitemia/imunologia , Plasmodium berghei/imunologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/parasitologia , Causalidade , Desidroepiandrosterona/metabolismo , Desidroepiandrosterona/farmacologia , Modelos Animais de Doenças , Estradiol/farmacologia , Feminino , Imunidade Inata/efeitos dos fármacos , Malária Cerebral/tratamento farmacológico , Camundongos , Camundongos Endogâmicos CBA , Neuroimunomodulação/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/imunologia , Óxido Nítrico Sintase Tipo I/metabolismo , Orquiectomia , Parasitemia/tratamento farmacológico , Parasitemia/fisiopatologia , Plasmodium berghei/efeitos dos fármacos , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Plasmodium berghei ANKA infection in CBA/J mice leads to the development of cerebral malaria (CM) that kills 80-90% of the animals in 6-9 days. This model has been used to study the pathogenesis of CM, which is a major cause of morbidity and mortality in Plasmodium falciparum-infected individuals. The role of cytokines in the induction of CM in the murine model has been well documented, but most studies have been restricted to the peak of neurological manifestations. Here we used a sequential approach to compare mice that developed CM with those that developed no cerebral pathology. Animals were examined for systemic histopathological changes and plasma Tumor Necrosis Factor-alpha (TNF) levels. The objectives were (a) to further determine the importance of factors commonly associated with murine CM-such as elevated levels of TNF and the presence of hemorrhage and vascular plugging-by comparing mice at different stages of infection and/or with different outcomes following infection and (b) to examine the importance of systemic changes-course of parasitemia and histopathological alterations in brain, liver, and lungs-in the development of CM. The data suggest that (a) the clinical manifestation of CM appears to be associated with a wave of merozoite release on days 6-7, (b) murine CM does not present reliable histopathological indicators, (c) there is no topographic association between the occurrence of intravascular plugging and the hemorrhagic foci, (d) monocyte-monocyte and monocyte-endothelial cell adherence were the most expressive histopathological events and were not restricted to brain vessels, (e) blood levels of TNF are not indicative of the local tissue reaction, (f) adhesiveness of monocyte/endothelial cells fluctuate during infection and is dissociated from the lymphocyte homing to the liver, and (g) pulmonary megakaryocytosis (megakaryopoiesis?) is a late event in the lungs.