RESUMEN
Sphingosine-1-phosphate (S1P) is a signaling lipid mediator that is involved in multiple biological processes. The S1P/S1P receptor (S1PR) signaling pathway has an important role in the central nervous system. It contributes to physiologic cellular homeostasis and is also associated with neuroinflammation. Therefore, this study was performed to evaluate the expression of S1PR in dogs with meningoencephalitis of unknown etiology (MUE) and experimental autoimmune encephalomyelitis (EAE). The analysis used 12 brain samples from three neurologically normal dogs, seven dogs with MUE, and two canine EAE models. Anti-S1PR1 antibody was used for immunohistochemistry. In normal brain tissues, S1PR1s were expressed on neurons, astrocytes, oligodendrocytes, and endothelial cells. In MUE and EAE lesions, there was positive staining of S1PR1 on leukocytes. Furthermore, the expression of S1PR1 on neurons, astrocytes, oligodendrocytes, and endothelial cells was upregulated compared to normal brains. This study shows that S1PR1s are expressed in normal brain tissues and leukocytes in inflammatory lesions, and demonstrates the upregulation of S1PR1 expression on nervous system cells in inflammatory lesions of MUE and EAE. These findings indicate that S1P/S1PR signaling pathway might involve physiologic homeostasis and neuroinflammation and represent potential targets for S1PR modulators to treat MUE.
Asunto(s)
Encéfalo , Enfermedades de los Perros , Encefalomielitis Autoinmune Experimental , Receptores de Esfingosina-1-Fosfato , Animales , Perros , Enfermedades de los Perros/metabolismo , Encefalomielitis Autoinmune Experimental/veterinaria , Encefalomielitis Autoinmune Experimental/metabolismo , Encéfalo/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Femenino , Masculino , Meningoencefalitis/veterinaria , Meningoencefalitis/metabolismo , Enfermedades Neuroinflamatorias/veterinaria , Enfermedades Neuroinflamatorias/metabolismo , Astrocitos/metabolismoRESUMEN
BACKGROUND/AIM: Tau is a microtubule-associated protein involved in the assembly and stabilization of microtubules. In human medicine, hyperphosphorylation of tau is associated with microtubule instability and is considered to play a role in the progression of multiple sclerosis (MS). MS is an autoimmune neurological disease that shares many characteristics, including pathological mechanisms, with canine meningoencephalitis of unknown etiology (MUE). With this background, this study investigated the presence of hyperphosphorylated tau in dogs with MUE and experimental autoimmune encephalomyelitis (EAE). MATERIALS AND METHODS: In total, eight brain samples were examined from two neurologically normal dogs, three dogs with MUE, and three canine EAE models. Anti-(phospho-S396) tau antibody was used for immunohisto-chemistry, which stained hyperphosphorylated tau. RESULTS: In normal brain tissues, hyperphosphorylated tau was not found. In all the dogs with EAE and one of the dogs with MUE, immunoreactivity for S396 p-tau was observed in glial cell cytoplasm and the background in the periphery of the inflammatory lesion. CONCLUSION: These results suggest for the first time that tau pathology may be involved in the progression of neuroinflammation in dogs, similar to that in human MS.
Asunto(s)
Meningoencefalitis , Esclerosis Múltiple , Animales , Perros , Encéfalo/patología , Meningoencefalitis/veterinaria , Meningoencefalitis/metabolismo , Meningoencefalitis/patología , Microtúbulos/metabolismo , Fosforilación , Proteínas tau/metabolismoRESUMEN
To improve the therapy of neonatal central nervous system infections, well-characterized animal models are urgently needed. The present study analyzes neuropathological alterations with particular focus on neural injury and repair in brains of neonatal mice with Listeria monocytogenes (LM) meningitis/meningoencephalitis using a novel nasal infection model. The hippocampal formation and frontal cortex of 14 neonatal mice with LM meningitis/meningoencephalitis and 14 uninfected controls were analyzed by histology, immunohistochemistry, and in situ tailing for morphological alterations. In the dentate gyrus of the hippocampal formation of mice with LM meningitis/meningoencephalitis, an increased density of apoptotic neurons visualized by in situ tailing (p = 0.04) and in situ tailing plus immunohistochemistry for activated Caspase-3 (p < 0.0001) was found. A decreased density of dividing cells stained with an anti-PCNA-antibody (p < 0.0001) and less neurogenesis visualized by anti-calretinin (p < 0.0001) and anti-calbindin (p = 0.01) antibodies were detected compared to uninfected controls. The density of microglia was higher in LM meningitis (p < 0.0001), while the density of astrocytes remained unchanged. Infiltrating monocytes and neutrophilic granulocytes likely contributed to tissue damage. In conclusion, in the brains of LM-infected mice a strong immune response was observed which led to neuronal apoptosis and an impaired neural regeneration. This model appears very suitable to study therapies against long-term sequelae of neonatal LM meningitis.
Asunto(s)
Lesiones Encefálicas/metabolismo , Encéfalo/metabolismo , Meningitis por Listeria/terapia , Meningoencefalitis/terapia , Enfermedades del Sistema Nervioso Periférico/terapia , Animales , Astrocitos/metabolismo , Calbindina 2/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Meningitis por Listeria/metabolismo , Meningoencefalitis/metabolismo , Ratones , Microglía/metabolismo , Neuropatología/métodos , Enfermedades del Sistema Nervioso Periférico/metabolismoRESUMEN
Peroxisome-proliferator activator receptor γ (PPARγ) has an anti-inflammatory role that inhibits the nuclear factor-κB (NF-κB) pathway and regulates the expressions of pro-inflammatory proteins, whereas its role in parasitic meningoencephalitis remains unknown. In this study we investigated the role of PPARγ and related mechanisms in eosinophilic meningoencephalitis caused by the rat lungworm Angiostrongylus cantonensis. We observed increased protein NF-κB expression in mouse brain tissue using GW9662, which is the specific antagonist of PPARγ, in a mouse model of angiostrongyliasis. Then we investigated NF-κB-related downstream proteins, such as COX-2, NOSs, and IL-1ß, with Western blot or enzyme-linked immunosorbent assay and found that the protein expression was upregulated. The results of gelatin zymography also showed that the MMP-9 activities were upregulated. Treatment with GW9662 increased the permeability of the blood-brain barrier and the number of eosinophils in cerebrospinal fluid. These results suggested that in angiostrongyliasis, PPARγ may play an anti-inflammation role in many inflammatory mediators, including NOS-related oxidative stress, cytokines, and matrix metalloproteinase cascade by decreasing the NF-κB action.
Asunto(s)
Angiostrongylus cantonensis/patogenicidad , Meningoencefalitis/metabolismo , Meningoencefalitis/parasitología , PPAR gamma/metabolismo , Infecciones por Strongylida/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Masculino , Metaloproteinasa 2 de la Matriz/líquido cefalorraquídeo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/líquido cefalorraquídeo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Distribución Aleatoria , Infecciones por Strongylida/parasitología , TaiwánAsunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Integrina alfa4/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Meningoencefalitis/tratamiento farmacológico , Natalizumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Integrina alfa4/inmunología , Integrina alfa4/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Masculino , Meningoencefalitis/inducido químicamente , Meningoencefalitis/inmunología , Meningoencefalitis/metabolismo , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Resultado del TratamientoRESUMEN
Meningoencephalitis is not a rare disease in small children. However, eosinophilic meningitis due to Angiostrongylus cantonensis is unusual in a baby. We describe the case of a 9-month-old baby from North Vietnam with eosinophilic meningoencephalitis. The baby lived in a rural area, where farming is widespread, and presented with fever and seizures. Laboratory results showed peripheral eosinophilia (16.1%), cerebrospinal fluid (CSF) white blood cell count 220/mm3 (26% eosinophils), CSF antibody test positive for Ascaris, CSF ELISA positive for Angiostrongylus cantonensis, and blood ELISA positive for A. cantonensis. A mobile worm was identified in the CSF. The presentation was consistent with a diagnosis of A. cantonensis eosinophilic meningitis. The baby recovered fully after administering albendazole (200 mg/day for 2 weeks), and intravenous dexamethasone (0.6 mg/kg/day every 8 hours) and mannitol (1.5 g/kg/day every 8 hours) for the first 3 days, followed by 5 days of oral prednisolone (2 mg/kg/day).
Asunto(s)
Angiostrongylus cantonensis/aislamiento & purificación , Eosinofilia/sangre , Meningoencefalitis/fisiopatología , Infecciones por Strongylida/fisiopatología , Albendazol/uso terapéutico , Animales , Antihelmínticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Anticuerpos Antihelmínticos/sangre , Anticuerpos Antihelmínticos/líquido cefalorraquídeo , Dexametasona/uso terapéutico , Diuréticos Osmóticos/uso terapéutico , Eosinofilia/etiología , Humanos , Lactante , Hipertensión Intracraneal/tratamiento farmacológico , Hipertensión Intracraneal/etiología , Imagen por Resonancia Magnética , Masculino , Manitol/uso terapéutico , Meningoencefalitis/complicaciones , Meningoencefalitis/tratamiento farmacológico , Meningoencefalitis/metabolismo , Prednisolona/uso terapéutico , Convulsiones/etiología , Convulsiones/fisiopatología , Infecciones por Strongylida/complicaciones , Infecciones por Strongylida/tratamiento farmacológico , Infecciones por Strongylida/metabolismo , Tomografía Computarizada por Rayos X , VietnamRESUMEN
Monocytes exist in two major populations, termed Ly6Chi and Ly6Clow monocytes. Compared to Ly6Chi monocytes, less is known about Ly6Clow monocyte recruitment and mechanisms involved in the recruitment of this subset. Furthermore, the role of Ly6Clow monocytes during infections is largely unknown. Here, using intravital microscopy, we demonstrate that Ly6Clow monocytes are predominantly recruited to the brain vasculature following intravenous infection with Cryptococcus neoformans, a fungal pathogen causing meningoencephalitis. The recruitment depends primarily on the interaction of VCAM1 expressed on the brain endothelium with VLA4 expressed on Ly6Clow monocytes. Furthermore, TNFR signaling is essential for the recruitment through enhancing VLA4 expression on Ly6Clow monocytes. Interestingly, the recruited Ly6Clow monocytes internalized C. neoformans and carried the organism while crawling on and adhering to the luminal wall of brain vasculature and migrating to the brain parenchyma. Our study reveals a substantial recruitment of Ly6Clow monocytes to the brain and highlights important properties of this subset during infection.
Asunto(s)
Criptococosis/inmunología , Monocitos/inmunología , Molécula 1 de Adhesión Celular Vascular/metabolismo , Animales , Encéfalo/inmunología , Criptococosis/metabolismo , Cryptococcus neoformans/metabolismo , Cryptococcus neoformans/patogenicidad , Modelos Animales de Enfermedad , Femenino , Integrina alfa4beta1/metabolismo , Masculino , Meningoencefalitis/metabolismo , Meningoencefalitis/microbiología , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo , Micosis/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVES: The aim of this study is to report a case series of atypical presentations of intracranial dysgerminoma in which the diagnosis was delayed due to clinical and radiographic findings initially suggestive of CNS inflammatory or demyelinating diseases, such as MS. METHODS: This study is a case series detailing the history, clinical presentations, radiographic and laboratory results, and management of three patients with biopsy-proven intracranial dysgerminoma. RESULTS: All three patients demonstrated hyperintense lesions on MRI that were more suggestive of demyelinating or inflammatory diseases, including lesions involving the midbrain and corpus callosum. All three patients were serum positive for oligoclonal bands and negative for both AFP and beta-hCG (these two markers are commonly seen in dysgerminoma cases). One case involved a steroid-responsive tumor whereas the other two cases either did not respond to steroids or steroids were withheld due to uncertainty of etiology. Following biopsy, all three results were consistent with dysgerminoma. CONCLUSION: Clinicians should be aware that dysgerminoma may mimic the clinical and radiographic presentations of demyelinating diseases such as MS. These lesions can cause acute visual loss or diplopia, have MRI and CSF findings that might mimic MS, and have been shown to respond to steroids. Atypical clinical (e.g., headache, dorsal midbrain syndrome, bilateral optic neuropathy) or atypical radiographic features (e.g., mass effect, hydrocephalus) should prompt consideration for repeat imaging and possible biopsy even if serum or CSF tumor markers (beta-hCG and AFP) are negative for dysgerminoma.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Enfermedades Desmielinizantes/diagnóstico por imagen , Disgerminoma/diagnóstico por imagen , Meningoencefalitis/diagnóstico por imagen , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Diagnóstico Diferencial , Disgerminoma/metabolismo , Disgerminoma/patología , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Meningoencefalitis/metabolismo , Meningoencefalitis/patología , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Estudios Retrospectivos , Pruebas del Campo Visual , Campos Visuales/fisiología , Adulto JovenRESUMEN
Proteasome primarily degrades the unneeded or damaged proteins by proteolysis. Disruption of the brain barrier and its resulting meningoencephalitis caused by Angiostrongylus cantonensis are important pathological events in non-permissive hosts. In this study, the results showed upregulated proteasome during A. cantonensis infection. Occludin degradation and matrix metalloproteinase-9 (MMP-9) activity were significantly increased in infected mice than in uninfected mice. Moreover, confocal immunoflourescence microscopy showed that occludin was co-localized with MMP-9. The infected-mice were treated with proteasomal activity inhibitor MG132 by 1.5 and 3.0 mg/kg/day, which resulted in significantly reduced protein levels of phosphorylated IκBα (P<0.05) compared with the untreated control. The phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) showed similar result. In addition, MMP-9 activity and occludin degradation were reduced because of MG132 treatment. These results suggested that the proteasome in A. cantonensis infection degraded phosphorylated IκBα, modulated phosphorylated NF-κB, and then regulated the activation of MMP-9 and occludin degradation. Proteasome alterations were presented in eosinophilic meningitis of BALB/c mice and may contribute to the pathophysiology of eosinophilic meningitis by increasing occludin degradation. This molecule would serve as pivotal regulator in A. cantonensis-induced eosinophilic meningoencephalitis.
Asunto(s)
Angiostrongylus cantonensis , Encéfalo/metabolismo , Meningoencefalitis/parasitología , Complejo de la Endopetidasa Proteasomal/metabolismo , Infecciones por Strongylida/metabolismo , Animales , Encéfalo/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Modelos Animales de Enfermedad , Leupeptinas/farmacología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Meningoencefalitis/metabolismo , Ratones , FN-kappa B/metabolismo , Ocludina/metabolismo , Fosforilación , Regulación hacia ArribaRESUMEN
The pathogenesis of tilapia meningoencephalitis is still unclear, where the involvement of circRNA is considered for its active role as a "miRNA sponge". Therefore, we aimed to investigate the profile of circRNA in tilapia meningoencephalitis further by constructing the circRNA-miRNA network for in-depth mechanism exploration. Briefly, a nile tilapia model of meningitis was established by injecting Streptococcus agalactiae (1.0 × 107 cfu per mL) and we evaluated the infected tilapia brain for the expression profile of circRNAs, their potential functions and their correlation with genes involved in inflammatory pathways. A total of 11 263 circRNAs were identified from RNA sequencing (RNA-seq) data in nile tilapia (Oreochromis niloticus), a commercially important fish in China and East Asia. GO and KEGG analyses revealed that the biological functions of genes hosting the circRNAs were enriched in the progression of metabolism and binding. Notably, we found that 99% circRNAs in tilapia had abundant miRNA-binding sites and a total of 2136 of the identified circRNAs had two to six miRNA-binding sites. Six circRNAs were validated by qRT-PCR and the final circRNA-miRNA network was constructed. This is the first report of comprehensive identification of O. niloticus circRNAs being differentially regulated in the brain in normal conditions relating to S. agalactiae infection. This work will shed novel light on gene expression mechanisms under disease conditions and may identify circRNAs as new biomarkers for meningoencephalitis and neurodegenerative disorders.
Asunto(s)
Cíclidos/metabolismo , Enfermedades de los Peces/metabolismo , Meningoencefalitis/veterinaria , MicroARNs/metabolismo , ARN Circular/metabolismo , Infecciones Estreptocócicas/veterinaria , Animales , Encéfalo/metabolismo , Cíclidos/genética , Biología Computacional , Enfermedades de los Peces/microbiología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Meningoencefalitis/metabolismo , Meningoencefalitis/microbiología , MicroARNs/genética , ARN Circular/genética , Infecciones Estreptocócicas/metabolismo , Infecciones Estreptocócicas/microbiología , Streptococcus agalactiaeRESUMEN
AIM: To examine the association between corticosteroid use in paediatric intensive care units (PICU) and subsequent symptoms of post-traumatic stress disorder (PTSD). METHODS: The subjects were children aged 8-16 years admitted to PICU with sepsis, meningoencephalitis (ME) and other disorders. Illness information was extracted from case notes; 3-6 months post discharge children completed a PTSD symptom questionnaire (eight-item Impact of Events Scale (IES-8)) assessing intrusion and avoidance symptoms. Saliva samples were also collected for cortisol profile analysis. RESULTS: 53 children completed the IES-8 questionnaires. 33 provided saliva samples. 19 (36%) received corticosteroids. In children with sepsis (n=15), corticosteroid use was associated with significantly lower PTSD intrusion symptom scores. There was a trend towards an association between corticosteroid use and lower evening cortisol levels. There was a comparable but weaker trend in children with ME. DISCUSSION: Corticosteroid use may be associated with fewer PTSD symptoms and lower evening cortisol levels following PICU admission in children with sepsis.
Asunto(s)
Cuidados Críticos/psicología , Glucocorticoides/uso terapéutico , Unidades de Cuidado Intensivo Pediátrico , Trastornos por Estrés Postraumático/etiología , Adolescente , Niño , Cuidados Críticos/métodos , Femenino , Estudios de Seguimiento , Humanos , Hidrocortisona/metabolismo , Tiempo de Internación/estadística & datos numéricos , Londres , Masculino , Meningoencefalitis/metabolismo , Meningoencefalitis/terapia , Saliva/metabolismo , Sepsis/metabolismo , Sepsis/terapia , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/prevención & controlRESUMEN
Cryptococcus neoformans is a basidiomycetous yeast and the cause of cryptococcosis in immunocompromised individuals. The most severe form of the disease is meningoencephalitis, which is one of the leading causes of death in HIV/AIDS patients. In order to access the central nervous system, C. neoformans relies on the activity of certain virulence factors such as urease, which allows transmigration through the blood-brain barrier. In this study, we demonstrate that the calcium transporter Pmc1 enables C. neoformans to penetrate the central nervous system, because the pmc1 null mutant failed to infect and to survive within the brain parenchyma in a murine systemic infection model. To investigate potential alterations in transmigration pathways in these mutants, global expression profiling of the pmc1 mutant strain was undertaken, and genes associated with urease, the Ca2+ -calcineurin pathway, and capsule assembly were identified as being differentially expressed. Also, a decrease in urease activity was observed in the calcium transporter null mutants. Finally, we demonstrate that the transcription factor Crz1 regulates urease activity and that the Ca2+ -calcineurin signalling pathway positively controls the transcription of calcium transporter genes and factors related to transmigration.
Asunto(s)
Sistema Nervioso Central/microbiología , Cryptococcus neoformans/metabolismo , Cryptococcus neoformans/patogenicidad , Proteínas Fúngicas/metabolismo , ATPasas Transportadoras de Calcio de la Membrana Plasmática/metabolismo , Animales , Transporte Biológico/fisiología , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/microbiología , Encéfalo/metabolismo , Encéfalo/microbiología , Calcineurina/metabolismo , Calcio/metabolismo , Línea Celular , Criptococosis/metabolismo , Criptococosis/microbiología , Modelos Animales de Enfermedad , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Meningoencefalitis/metabolismo , Meningoencefalitis/microbiología , Ratones , Ratones Endogámicos BALB C , Vacuolas/metabolismo , Vacuolas/microbiología , Virulencia/fisiología , Factores de Virulencia/metabolismoRESUMEN
Bovine herpesvirus 5 (BHV5) infection of young cattle is frequently associated with fatal neurological disease and, as such, represents an attractive model for studying the pathogenesis of viral-induced meningoencephalitis. Following replication in the nasal mucosa, BHV5 invades the central nervous system (CNS) mainly through the olfactory pathway. The innate immune response triggered by the host face to virus replication through the olfactory route is poorly understood. Recently, an upregulation of conserved pathogen-associated molecular pattern, as Toll-like receptors (TLRs), has been demonstrated in the CNS of BHV5 experimentally infected cows. A new perspective to understand host-pathogen interactions has emerged elucidating microRNAs (miRNAs) network that interact with innate immune response during neurotropic viral infections. In this study, we demonstrated a link between the expression of TLRs 3, 7, and 9 and miR-155 transcription in the olfactory bulbs (OB) of 16 cows suffering from acute BHV5-induced neurological disease. The OBs were analyzed for viral antigens and genome, miR-155 and TLR 3, 7, and 9 expression considering three major regions: olfactory receptor neurons (ORNs), glomerular layer (GL), and mitral cell layer (ML). BHV5 antigens and viral genomes, corresponding to glycol-C gene, were detected in all OBs regions by fluorescent antibody assay (FA) and PCR, respectively. TLR 3, 7, and 9 transcripts were upregulated in ORNs and ML, yet only ORN layers revealed a positive correlation between TLR3 and miR-155 transcription. In ML, miR-155 correlated positively with all TLRs studied. Herein, our results evidence miR-155 transcription in BHV5 infected OB tissue associated to TLRs expression specifically ORNs which may be a new window for further studies.
Asunto(s)
Encefalitis Viral/metabolismo , Infecciones por Herpesviridae/metabolismo , Meningoencefalitis/metabolismo , MicroARNs/metabolismo , Receptores Toll-Like/biosíntesis , Animales , Bovinos , Femenino , Regulación de la Expresión Génica , Herpesvirus Bovino 5 , Bulbo Olfatorio/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , Receptor Toll-Like 3/biosíntesis , Receptor Toll-Like 7/biosíntesis , Receptor Toll-Like 9/biosíntesis , Transcripción GenéticaRESUMEN
The role of suppressors of cytokine signaling (SOCS) in meningoencephalitis caused by Bovine herpesvirus 5 (BoHV-5) was evaluated by intracranial infection in C57BL/6 wild-type mice (WT) and SOCS2 deficient mice (SOCS2(-/-)). Both infected groups presented weight loss, ruffled fur and hunched posture. Additionally, infected SOCS2(-/-) mice showed swollen chamfer and progressive depression. Infected WT animals developed mild meningitis, characterized by infiltration of mononuclear cells. Moreover, viral DNA was detected in liver and lung from infected WT group. This group also showed elevated brain levels of IFN-γ, IL-10, CXCL1 and CCL5, when compared with non-infected WT animals. Brain inflammation was exacerbated in infected SOCS2(-/-) mice with widespread distribution of the virus and increased brain levels of TNF-α, IFN-γ, IL-10, IL-12, CXCL1 and CCL5, when compared with WT infected mice. Moreover, infected SOCS2 deficient mice exhibited reduced brain mRNA expression of IFNα and IFNß and increased expression of mRNA of SOCS1, compared with infected WT mice. Taken together, our study provides an insight into the role of SOCS2 in modulating the immune response to BoHV-5 infection.
Asunto(s)
Encéfalo/virología , Infecciones por Herpesviridae/veterinaria , Herpesvirus Bovino 5/genética , Herpesvirus Bovino 5/patogenicidad , Meningoencefalitis/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/fisiología , Animales , Encéfalo/inmunología , Encéfalo/fisiopatología , Bovinos , Quimiocina CCL5/genética , Quimiocina CXCL1/genética , Citocinas/genética , ADN Viral , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/fisiopatología , Infecciones por Herpesviridae/virología , Herpesvirus Bovino 5/inmunología , Interferón-alfa/genética , Interferón beta/genética , Hígado/virología , Pulmón/virología , Meningoencefalitis/inmunología , Meningoencefalitis/fisiopatología , Meningoencefalitis/virología , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Proteínas Supresoras de la Señalización de Citocinas/deficiencia , Proteínas Supresoras de la Señalización de Citocinas/inmunologíaRESUMEN
Herpes simplex virus type 1 (HSV-1) is a human pathogen that may cause severe encephalitis. The exacerbated immune response against the virus contributes to the disease severity and death. Platelet activating factor (PAF) is a mediator capable of inducing increase in vascular permeability, production of cytokines on endothelial cells and leukocytes. We aimed to investigate the activation of PAF receptor (PAFR) and its contribution to the severity of the inflammatory response in the brain following HSV-1 infection. C57BL/6 wild-type (WT) and PAFR deficient (PAFR-/-) mice were inoculated intracranially with 104 plaque-forming units (PFU) of HSV-1. Visualization of leukocyte recruitment was performed using intravital microscopy. Cells infiltration in the brain tissue were analyzed by flow cytometry. Brain was removed for chemokine assessment by ELISA and for histopathological analysis. The pharmacological inhibition by the PAFR antagonist UK-74,505 was also analyzed. In PAFR-/- mice, there was delayed lethality but no difference in viral load. Histopathological analysis of infected PAFR-/- mice showed that brain lesions were less severe when compared to their WT counterparts. Moreover, PAFR-/- mice showed less TCD4+, TCD8+ and macrophages in brain tissue. This reduction of the presence of leukocytes in parenchyma may be mechanistically explained by a decrease in leukocytes rolling and adhesion. PAFR-/- mice also presented a reduction of the chemokine CXCL9 in the brain. In addition, by antagonizing PAFR, survival of C57BL/6 infected mice increased. Altogether, our data suggest that PAFR plays a role in the pathogenesis of experimental HSV-1 meningoencephalitis, and its blockade prevents severe disease manifestation.
Asunto(s)
Herpes Simple/metabolismo , Herpesvirus Humano 1 , Meningoencefalitis/metabolismo , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Glicoproteínas de Membrana Plaquetaria/deficiencia , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/deficiencia , Índice de Severidad de la Enfermedad , Animales , Encéfalo/patología , Encéfalo/virología , Dihidropiridinas/farmacología , Dihidropiridinas/uso terapéutico , Herpes Simple/patología , Herpes Simple/prevención & control , Imidazoles/farmacología , Imidazoles/uso terapéutico , Masculino , Meningoencefalitis/patología , Meningoencefalitis/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
INTRODUCTION: Viral encephalitis is an emerging disease requiring intensive care management in severe cases. Underlying pathophysiologic mechanisms are incompletely understood and may be elucidated using invasive multimodal neuromonitoring techniques in humans. METHODS: Two otherwise healthy patients were admitted to our neurological intensive care unit with altered level of consciousness necessitating mechanical ventilation. Brain imaging and laboratory workup suggested viral encephalitis in both patients. Invasive neuromonitoring was initiated when head computed tomography revealed generalized brain edema, including monitoring of intracranial pressure, brain metabolism (cerebral microdialysis; CMD), brain tissue oxygen tension (in one patient), and cerebral blood flow (in one patient). RESULTS: Brain metabolism revealed episodes of severe neuroglucopenia (brain glucose <0.7 mM/l) in both patients, which were not attributable to decreased cerebral perfusion or hypoglycemia. CMD-glucose levels changed depending on variations in insulin therapy, nutrition, and systemic glucose administration. The metabolic profile, moreover, showed a pattern of non-ischemic metabolic distress suggestive for mitochondrial dysfunction. Both patients had a prolonged but favorable clinical course and improved to a modified Rankin Scale Score of 1 and 0 three months later. CONCLUSION: Invasive multimodal neuromonitoring is feasible in poor-grade patients with viral meningoencephalitis and may help understand pathophysiologic mechanisms associated with secondary brain injury. The detection of neuroglucopenia and mitochondrial dysfunction may serve as treatment targets in the future.
Asunto(s)
Encefalitis Viral/metabolismo , Glucosa/metabolismo , Meningoencefalitis/metabolismo , Monitorización Neurofisiológica/métodos , Adolescente , Adulto , Femenino , Humanos , Masculino , MicrodiálisisRESUMEN
Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide evidence for regeneration promoting cells recruitable for therapeutic purposes. There is evidence that neurotrophin receptor p75 (p75NTR)-expressing cells emerge in the lesioned CNS. However, the phenotype and identity of these cells, and signals triggering their in situ generation under normal conditions and certain pathological situations has remained enigmatic. In the present study, we used a spontaneous, idiopathic and inflammatory CNS condition in dogs with prominent lympho-histiocytic infiltration as a model to study the phenotype of Schwann cells and their relation to Schwann cell remyelination within the CNS. Furthermore, the phenotype of p75NTR-expressing cells within the injured CNS was compared to their counter-part in control sciatic nerve and after peripheral nerve injury. In addition, organotypic slice cultures were used to further elucidate the origin of p75NTR-positive cells. In cerebral and cerebellar white and grey matter lesions as well as in the brain stem, p75NTR-positive cells co-expressed the transcription factor Sox2, but not GAP-43, GFAP, Egr2/Krox20, periaxin and PDGFR-α. Interestingly, and contrary to the findings in control sciatic nerves, p75NTR-expressing cells only co-localized with Sox2 in degenerative neuropathy, thus suggesting that such cells might represent dedifferentiated Schwann cells both in the injured CNS and PNS. Moreover, effective Schwann cell remyelination represented by periaxin- and P0-positive mature myelinating Schwann cells, was strikingly associated with the presence of p75NTR/Sox2-expressing Schwann cells. Intriguingly, the emergence of dedifferentiated Schwann cells was not affected by astrocytes, and a macrophage-dominated inflammatory response provided an adequate environment for Schwann cells plasticity within the injured CNS. Furthermore, axonal damage was reduced in brain stem areas with p75NTR/Sox2-positive cells. This study provides novel insights into the involvement of Schwann cells in CNS remyelination under natural occurring CNS inflammation. Targeting p75NTR/Sox2-expressing Schwann cells to enhance their differentiation into competent remyelinating cells appears to be a promising therapeutic approach for inflammatory/demyelinating CNS diseases.
Asunto(s)
Meningoencefalitis/metabolismo , Vaina de Mielina/metabolismo , Regeneración Nerviosa , Animales , Estudios de Casos y Controles , Perros , Meningoencefalitis/patología , Meningoencefalitis/veterinaria , Vaina de Mielina/patología , Vaina de Mielina/fisiología , Receptores de Factor de Crecimiento Nervioso/genética , Receptores de Factor de Crecimiento Nervioso/metabolismo , Factores de Transcripción SOXB1/metabolismoRESUMEN
In this study, the expression levels of viral Toll-like receptors (TLRs) in the nervous system of bovine herpesvirus type 5 (BoHV-5)-infected calves were investigated. A significant increase in the expression of TLRs 3 and 7-9 was found in the anterior cerebral cortex during acute infection and viral reactivation. In the trigeminal ganglia, only TLR9 expression was significantly affected. The magnitude of the increase was lower in BoHV-1-infected calves, suggesting that a restricted immune response might protect against exacerbated inflammatory responses in the brain. This work describes, for the first time, the involvement of TLRs 3 and 7-9 in the recognition of BoHV in the bovine nervous system, indicating that the expression of these receptors might be associated with the development of neurological disease. Modulation of the signalling pathways mediated by TLRs might provide an effective approach to control the neuro-immune response to BoHV-5, which may be responsible for neurological lesions.
Asunto(s)
Enfermedades de los Bovinos/metabolismo , Enfermedades de los Bovinos/virología , Encefalitis Viral/veterinaria , Infecciones por Herpesviridae/veterinaria , Herpesvirus Bovino 5/patogenicidad , Meningoencefalitis/veterinaria , Sistema Nervioso/metabolismo , Receptores Toll-Like/metabolismo , Administración Intranasal , Animales , Bovinos , Enfermedades de los Bovinos/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/virología , ADN Viral/metabolismo , Encefalitis Viral/metabolismo , Encefalitis Viral/patología , Infecciones por Herpesviridae/metabolismo , Infecciones por Herpesviridae/patología , Herpesvirus Bovino 5/genética , Herpesvirus Bovino 5/aislamiento & purificación , Meningoencefalitis/metabolismo , Meningoencefalitis/patología , Sistema Nervioso/patología , Sistema Nervioso/virología , Transducción de Señal , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , Receptor Toll-Like 9/metabolismo , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/patología , Ganglio del Trigémino/virologíaRESUMEN
Inflammation is a normal host defense reaction to infections and tissue injury. In pathology, the process of inflammation is deregulated by various environmental factors, prolonged activation of Toll-like receptors (TLRs), induction of epigenetic machinery or expression of receptors for advanced glycation end-products (RAGE). In the present study, we examined immunoexpression of proteins participating in the above-mentioned mechanisms, in the brain of patients with viral meningoencephalitis. The results showed that depending on the period of the disease, the process of inflammation is deregulated in different ways. In an early period of viral meningoencephalitis, we found numerous so-called microglial nodules which were strongly immunopositive to methyl-CpG protein 2 (MeCP2). This protein is an epigenetic factor important for methylation of DNA; therefore, our results suggest that cells collected in the nodules may participate in modification of the host defense reaction. Moreover, in the early period of viral meningoencephalitis, we found that Purkinje cells of the cerebellum contain TLR3 or TLR9 receptors that can recognize viral pathogens and may activate a self-destructive mechanism in these neurons. In the later (advanced) period of viral meningoencephalitis, despite some of the above observations, RAGE protein was detected in the brain of adult and aging patients. It means that in this period of the disease, the inflammatory process may be deregulated by numerous post-translationally modified proteins that are transported to the brain after binding with activated RAGE. In addition, young patients appeared more susceptible to viral infections than adult and aging patients, because most of them died during the early period of meningoencephalitis.
Asunto(s)
Inmunidad Innata/inmunología , Meningoencefalitis/virología , Proteína 2 de Unión a Metil-CpG/metabolismo , Adulto , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Inflamación/inmunología , Meningoencefalitis/metabolismo , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 9/metabolismo , Adulto JovenRESUMEN
PURPOSE: Complement regulators control the activated complement system. Defects in this homeostasis can result in tissue damage and autoimmune diseases with a heterogeneity in clinical presentation. Complement factor I (FI), a serine protease, is an important regulator of alternative pathway activation. We report a diagnostic work-up of a patient with relapsing inflammatory mediated meningo-encephalitis. Our work-up revealed a rare genetic factor I (FI) deficiency. So far, all cases of reported complete factor I deficiency have absent serum levels of FI. We present here a unique case of a complete factor I deficiency based on a functional FI defect. METHODS: Complement assays and measurement of FI activity were performed in the patient, her family, factor H-deficient patients, a patient with C3-nephritic factor and 11 healthy controls. Genetic sequencing of the FI coding regions in the patient and her parents was performed. RESULTS: The patient had absent alternative pathway activity with low levels of C3 and normal serum level of FI. The patient's plasma FI did not degrade C3b, with normalisation of C3b degradation after adding purified FI. Mutation analysis of the complement factor I gene revealed two heterozygous mutations (I322T and D506V). CONCLUSION: To our knowledge, this paper describes a complete FI deficiency caused by a defect of FI activity for the first time. Normal FI concentration does not exclude a complete FI defect, additional functional analysis of FI is required in any patient with a defect of complement activation. Recurrent aseptic meningo-encephalitis is a rare clinical presentation of complete FI deficiency.