RESUMEN
Paracoccidioidomycosis (PCM), a chronic granulomatous disease caused by the thermally dimorphic fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii, has the highest mortality rate among systemic mycosis. The T helper 1-mediated immunity is primarily responsible for acquired resistance during P. brasiliensis infection, while susceptibility is associated with Th2 occurrence. Th17 is a population of T CD4+ cells that, among several chemokines and cytokines, produces IL-17A and requires the presence of IL-1, IL-6, and TGF-ß for differentiation in mice and IL-23 for its maintenance. Th17 has been described as an arm of the immune system that enhances host protection against several bacterial and fungal infections, as Pneumocystis carinii and Candida albicans. In this study, we aimed to evaluate the Th17 immune response and the role of Th17-associated cytokines (IL-6, IL-23, and IL-17A) during experimental PCM. First, we observed that P. brasiliensis infection [virulent yeast strain 18 of P. brasiliensis (Pb18)] increased the IL-17A production in vitro and all the evaluated Th17-associated cytokines in the lung tissue from C57BL/6 wild-type mice. In addition, the deficiency of IL-6, IL-23, or IL-17 receptor A (IL-17RA) impaired the compact granuloma formation and conferred susceptibility during infection, associated with reduced tumor necrosis factor-α, IFN-γ, and inducible nitric oxide synthase enzyme expression. Our data suggest that IL-6 production by bone marrow-derived macrophages (BMDMs) is important to promote the Th17 differentiation during Pb18 infection. In accordance, the adoptive transfer of BMDMs from C57BL/6 to infected IL-6-/- or IL-17RA-/- mice reduced the fungal burden in the lungs compared to nontransferred mice and reestablished the pulmonary granuloma formation. Taken together, these results suggest that Th17-associated cytokines are involved in the modulation of immune response and granuloma formation during experimental PCM.
RESUMEN
Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons accompanied by an inflammatory reaction. The neuron-derived chemokine fractalkine (CX3CL1) is an exclusive ligand for the receptor CX3CR1 expressed on microglia. The CX3CL1/CX3CR1 signaling is important for sustaining microglial activity. Using a recently developed PD model, in which the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin is delivered intranasally, we hypothesized that CX3CR1 could play a role in neurotoxicity and glial activation. For this, we used CX3CR1 knock-in mice and compared results with those obtained using the classical PD models through intraperitonal MPTP or intrastriatal 6-hydroxydopamine (6-OHDA). The striatum from all genotypes (CX3CR1(+/+), CX3CR1(+/GFP) and CX3CR1-deficient mice) showed a significant dopaminergic depletion after intranasal MPTP inoculation. In contrast to that, we could not see differences in the number of dopaminergic neurons in the substantia nigra of CX3CR1-deficient animals. Similarly, after 6-OHDA infusion, the CX3CR1 deletion decreased the amphetamine-induced turning behavior observed in CX3CR1(+/GFP) mice. After the 6-OHDA inoculation, a minor dopaminergic neuronal loss was observed in the substantia nigra from CX3CR1-deficient mice. Distinctly, a more extensive neuronal cell loss was observed in the substantia nigra after the intraperitoneal MPTP injection in CX3CR1 disrupted animals, corroborating previous results. Intranasal and intraperitoneal MPTP inoculation induced a similar microgliosis in CX3CR1-deficient mice but a dissimilar change in the astrocyte proliferation in the substantia nigra. Nigral astrocyte proliferation was observed only after intraperitoneal MPTP inoculation. In conclusion, intranasal MPTP and 6-OHDA lesion in CX3CR1-deficient mice yield no nigral dopaminergic neuron loss, linked to the absence of astroglial proliferation.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Oxidopamina/toxicidad , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Receptores de Quimiocina/metabolismo , Sustancia Negra/efectos de los fármacos , Administración Intranasal , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Receptor 1 de Quimiocinas CX3C , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Encefalitis/inducido químicamente , Encefalitis/metabolismo , Gliosis/inducido químicamente , Gliosis/metabolismo , Inyecciones Intraperitoneales , Ratones , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/metabolismo , Trastornos Parkinsonianos/inducido químicamente , Receptores de Quimiocina/genética , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
INTRODUCTION: Exercise improves the motor symptoms of patients with Parkinson disease in a palliative manner. Existing evidence demonstrates that exercise induces neuroprotection based on the neurotrophic properties. We investigated the effect of exercise on mitochondrial physiology and oxidative stress in an animal model of hemiparkinsonism. METHODS: C57BL/6 mice completed a 6-week exercise program on a treadmill. We injected 6-hydroxydopamine (6-OHDA; 4 µg/2 µl) into the midstriatum. The animals progressively developed bradykinesia and R(-)-apomorphine-induced rotations that were attenuated by exercise. Transcriptional activation of protective genes is mediated by the antioxidant response element (ARE). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) binds to ARE. We investigated the Nrf2-ARE pathway in the striatum of animals. RESULTS: Exercise protected 6-OHDA-induced loss of tyrosine hydroxylase immunolabeling and activated the Nrf2-ARE pathway in the nigrostriatal pathway. Exercise stimulated mitochondrial biogenesis in the striatum of animals that was more resistant to oxidant 6-OHDA and nitric oxide donor (±)-S-nitroso-N-acetylpenicillamine. CONCLUSIONS: In mice, exercise activated Nrf2-ARE signaling in the nigrostriatal pathway that was protective against the development of hemiparkinsonism.
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Factor 2 Relacionado con NF-E2/metabolismo , Oxidopamina/toxicidad , Trastornos Parkinsonianos/prevención & control , Condicionamiento Físico Animal , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos Parkinsonianos/etiología , Trastornos Parkinsonianos/metabolismoRESUMEN
Exercise improves the central nervous system (CNS) functions and is widely recommended for neurological patients with, e.g., Alzheimer's and Parkinson's disease (PD). However, exercise-induced neuroprotection is an open discussion. Here, the intranasal administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 65 mg/kg) caused death of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the striatum of C57BL/6 mice. 1-Methyl-4-phenylpyridinium, the active metabolite of MPTP, also inhibited complex-I activity of mitochondria isolated from the CNS of mice. However, 6 weeks of exercise on voluntary running wheels did not protect against nigrostriatal neurodegeneration or mitochondrial inhibition, suggesting that benefits of exercise for PD may not be associated with neuroprotection. The literature presents other candidates, such as neurotrophins or increased antioxidant defenses.
Asunto(s)
Intoxicación por MPTP/prevención & control , Condicionamiento Físico Animal , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , 1-Metil-4-fenilpiridinio/administración & dosificación , Administración Intranasal , Animales , Cuerpo Estriado/química , Cuerpo Estriado/efectos de los fármacos , Dopamina/análisis , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/enzimología , Mitocondrias/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the thermodimorphic fungus Paracoccidioides brasiliensis. Leukotrienes and lipoxins are lipid mediators produced after 5-lipoxygenase (5-LO) activation that exhibit pro- and anti-inflammatory roles, respectively. Here, we have investigated the contribution of 5-LO enzymatic activity in PCM using an experimental model of P. brasiliensis infection. B6.129 wild-type (B6.129) and 5-LO-deficient (5-LO(-/-)) mice were intravenously inoculated with a virulent strain of P. brasiliensis (Pb18), and the survival rate of the infected mice was investigated on different days after yeast infection. 5-LO(-/-) mice exhibited an increased survival rate associated with a decreased number of CFU. The resistance of 5-LO(-/-) during PCM was associated with augmented nitric oxide (NO) production and the formation of compact granulomas. In addition, the absence of 5-LO was associated with a diminished number of CD4(+) CD25(+) regulatory T cells, higher levels of gamma interferon and interleukin-12, and increased T-bet (a T-box transcription factor that directs Th1 lineage commitment) mRNA levels in the lungs. Taken together, our results show for the first time that 5-LO enzymatic activity increases susceptibility to P. brasiliensis, suggesting that this pathway may be a potential target for therapeutic intervention during PCM.
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Paracoccidioides/patogenicidad , Paracoccidioidomicosis/microbiología , Paracoccidioidomicosis/mortalidad , Animales , Araquidonato 5-Lipooxigenasa/deficiencia , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Granuloma/microbiología , Granuloma/patología , Interferón gamma/biosíntesis , Interleucina-12/biosíntesis , Masculino , Ratones , Ratones Noqueados , Óxido Nítrico/metabolismo , Paracoccidioidomicosis/patología , Análisis de Supervivencia , Proteínas de Dominio T Box/biosíntesis , Linfocitos T Reguladores/inmunología , Factores de TiempoRESUMEN
INTRODUCTION: During histoplasmosis, Histoplasma capsulatum soluble antigens (CFAg) can be naturally released by yeast cells. Because CFAg can be specifically targeted during infection, in the present study we investigated CFAg release in experimental murine histoplasmosis, and evaluated the host humoral immune response against high-molecular-mass antigens (hMMAg. >150 kDa), the more immunogenic CFAg fraction. METHODS: Mice were infected with 2.2 x 104 H. capsulatum IMT/HC128 yeast cells. The soluble CFAg, IgG anti-CFAg, IgG anti-hMMAg, and IgG-hMMAg circulating immune complexes (CIC) levels were determined by enzymelinked immunosorbent assay, at days 0, 7, 14, and 28 post-infection. RESULTS: We observed a progressive increase in circulating levels of CFAg, IgG anti-CFAg, IgG anti-hMMAg, and IgG-hMMAg CIC after H. capsulatum infection. The hMMAg showed a high percentage of carbohydrates and at least two main immunogenic components. CONCLUSIONS: We verified for the first time that hMMAg from H. capsulatum IMT/HC128 strain induce humoral immune response and lead to CIC formation during experimental histoplasmosis.
Asunto(s)
Anticuerpos Antifúngicos/inmunología , Antígenos Fúngicos/inmunología , Carbohidratos/inmunología , Histoplasma/inmunología , Histoplasmosis/inmunología , Inmunidad Humoral/inmunología , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Masculino , Ratones , Peso MolecularRESUMEN
INTRODUCTION: During histoplasmosis, Histoplasma capsulatum soluble antigens (CFAg) can be naturally released by yeast cells. Because CFAg can be specifically targeted during infection, in the present study we investigated CFAg release in experimental murine histoplasmosis, and evaluated the host humoral immune response against high-molecular-mass antigens (hMMAg. >150 kDa), the more immunogenic CFAg fraction. METHODS: Mice were infected with 2.2x10(4) H. capsulatum IMT/HC128 yeast cells. The soluble CFAg, IgG anti-CFAg, IgG anti-hMMAg, and IgG-hMMAg circulating immune complexes (CIC) levels were determined by enzymelinked immunosorbent assay, at days 0, 7, 14, and 28 post-infection. RESULTS: We observed a progressive increase in circulating levels of CFAg, IgG anti-CFAg, IgG anti-hMMAg, and IgG-hMMAg CIC after H. capsulatum infection. The hMMAg showed a high percentage of carbohydrates and at least two main immunogenic components. CONCLUSIONS: We verified for the first time that hMMAg from H. capsulatum IMT/HC128 strain induce humoral immune response and lead to CIC formation during experimental histoplasmosis.
INTRODUÇÃO: Durante a histoplasmose, os antígenos solúveis de Histoplasma capsulatum (CFAg) podem ser liberados naturalmente pelas células leveduriformes. Considerando que os CFAg constituem um alvo específico durante a infecção, no presente estudo nós investigamos a liberação de CFAg durante a histoplasmose murina experimental, e avaliamos a resposta imune humoral do hospedeiro contra antígenos de alta MM (hMMAg; >150 kDa), altamente imunogênicos. MÉTODOS: Camundongos foram infectados com 2.2x10(4) leveduras de H. capsulatum, cepa IMT/HC128. Os níveis de CFAg solúveis, IgG anti-CFAg, IgG anti-hMMAg, e também de imunocomplexos circulantes (CIC) IgG-hMMAgs foram determinados por ELISA nos dias 0, 7, 14 e 28 após a infecção. RESULTADOS: Após a infecção por H. capsulatum, observamos um aumento progessivo de CFAg circulantes, IgG anti-CFAg, IgG anti-hMMAg, e também de CIC IgG-hMMAgs. Os hMMAg apresentaram alta porcentagem de carboidratos e, pelo menos, dois componentes imunogênicos. CONCLUSÕES: Mostramos pela primeira vez que os hMMAg de H. capsulatum cepa IMT/HC128 induzem resposta imune humoral e levam à formação de CIC durante a histoplasmose experimental.
Asunto(s)
Animales , Masculino , Ratones , Anticuerpos Antifúngicos/inmunología , Antígenos Fúngicos/inmunología , Carbohidratos/inmunología , Histoplasma/inmunología , Histoplasmosis/inmunología , Inmunidad Humoral/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Peso MolecularRESUMEN
O TT vírus (TTV) foi primeiramente descrito no Japão, em 1997, por T. Nishizawa, no soro de pacientes com hepatite, pós-transfusão, não-A-G. Tem sido intensivamente investigado, desde então, como uma possível adicão à lista dos vírus indutores de hepatite. O TTV é um vírus DNA não-envelopado, de fita simples. Uma considerável variabilidade genética tem sido demonstrada por parte do TTV, o que tem levado pesquisadores a agrupar isolados do vírus em inúmeros genótipos e subtipos. No entanto a significância clínica da infeccão por TTV permanece desconhecida. Ele é freqüentemente detectado em fluidos corporais e seu componente mais bem elucidado atualmente é o genoma. Conhecimentos relacionados ao TTV têm aumentado constantemente, porém vários aspectos fundamentais permanecem obscuros. Esta revisão apresenta algumas das propriedades moleculares do TT vírus.