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Zika virus (ZIKV) disease continues to be a threat to public health, and it is estimated that millions of people have been infected and that there have been more cases of serious complications than those already reported. Despite many studies on the pathogenesis of ZIKV, several of the genes involved in the malformations associated with viral infection are still unknown. In this work, the morphological and molecular changes in the cortex and cerebellum of mice infected with ZIKV were evaluated. Neonatal BALB/c mice were inoculated with ZIKV intraperitoneally, and the respective controls were inoculated with a solution devoid of the virus. At day 10 postinoculation, the mice were euthanized to measure the expression of the markers involved in cortical and cerebellar neurodevelopment. The infected mice presented morphological changes accompanied by calcifications, as well as a decrease in most of the markers evaluated in the cortex and cerebellum. The modifications found could be predictive of astrocytosis, dendritic pathology, alterations in the regulation systems of neuronal excitation and inhibition, and premature maturation, conditions previously described in other models of ZIKV infection and microcephaly.
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Infección por el Virus Zika , Virus Zika , Animales , Ratones , Cerebelo , Gliosis , Ratones Endogámicos BALB CRESUMEN
Bovine alphaherpesviruses (BoHV) 1 and 5 share many genetic and structural characteristics; however, they differ in their ability to cause encephalitis. Previous research suggests that this difference might be caused by a differential modulation of apoptosis. In this study, we analyzed the mRNA expression of Bax, Bcl-2, Fas and caspases 3 and 8 in neural tissue sections of BoHV-1 and BoHV-5 experimentally-infected cattle. Overall, Fas and caspase 3 mRNA was up-regulated during BoHV-5 acute infection, latency, and reactivation. Conversely, caspase 3 mRNA levels increased only in the olfactory cortex during BoHV-1 acute infection, and it was down-regulated during reactivation, while Fas was only up-regulated during BoHV-1 acute infection and latency. Moreover, Bax/Bcl-2 ratio was lower than 1 during BoHV-1 acute infection except in the trigeminal ganglion, whereas many brain regions exhibit a ratio higher than 1 during BoHV-5 acute infection and reactivation. In summary, our findings suggest that during acute infection and reactivation, BoHV-5 induces a pro-apoptotic condition that could partially justify its increased ability to cause neurological damage.
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Enfermedades de los Bovinos , Infecciones por Herpesviridae , Herpesvirus Bovino 1 , Animales , Bovinos , Herpesvirus Bovino 1/genética , Caspasa 3/genética , Caspasa 3/metabolismo , Infecciones por Herpesviridae/veterinaria , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Apoptosis/genética , ARN Mensajero/genéticaRESUMEN
The transactivator of transcription (Tat) is a key HIV regulatory protein. We aimed to identify the frequency of key polymorphisms in HIV-1C compared with HIV-1B Tat protein, chiefly in the cysteine-, arginine-, and glutamine-rich domains and identify novel point mutations in HIV-1B and C sequences from Southern Brazil. This study was the first to investigate the genetic diversity and point mutations within HIV-1 Tat C in a Brazilian cohort. This was an observational, cross-sectional study, which included sequences of HIV-1B (n = 20) and HIV-1C (n = 21) from Southern Brazil. Additionally, 344 HIV-1C sequences were obtained from the Los Alamos database: 29 from Brazil and 315 from Africa, Asia, and Europe. The frequency of C31S substitution on HIV-1 Tat C in Brazil was 82% vs. 10% in the HIV-1B group (p < 0.0001). The frequency of the R57S substitution among the HIV-1C sequences from Brazil was 74% vs. 20% in HIV-1B (p = 0.004), and that of substitution Q63E in HIV-1C was 80% and 20% in HIV-1B (p < 0.0001). The mutation P60Q was more frequent in HIV-1B than in HIV-1C (55% and 6.12%, respectively, p < 0.0001)). Novel point mutations in the HIV-1C and B Tat functional domains were described. The frequency of C31S and other key point mutations in HIV-1 Tat C in Brazil were similar to those described in Africa, although lower than those in India. The Tat-B and C sequences found in Southern Brazil are consistent with biological differences and have potential implications for HIV-1 subtype pathogenesis.
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VIH-1/genética , Polimorfismo de Nucleótido Simple/genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética , Adulto , Brasil , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Dengue is an arboviral disease caused by dengue virus (DENV), which is transmitted to humans by Aedes aegypti mosquitoes. Infection by DENV most commonly results in a mild flu-like illness; however, the disease has been increasingly associated with neurological symptomatology. This association draws attention to further investigations on the impact of DENV infection in the host's central nervous system. Here, we analyzed brain samples of three fatal dengue cases that occurred in 2002 during an outbreak in Rio de Janeiro, Brazil. Brain tissues of these cases were marked by histopathological alterations, such as degenerated neurons, demyelination, hemorrhage, edema, and increased numbers of astrocytes and microglial cells. Samples were also characterized by lymphocytic infiltrates mainly composed of CD8 T cells. DENV replication was evidenced in neurons, microglia and endothelial cells through immunohistochemistry and in situ hybridization techniques. Pro-inflammatory cytokines, such as TNF-α and IFN-γ were detected in microglia, while endothelial cells were marked by the expression of RANTES/CCL5. Cytoplasmic HMGB1 and the production of nitric oxide were also found in neurons and microglial cells. This work highlights the possible participation of several local pro-inflammatory mediators in the establishment of dengue neuropathogenesis.
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Encéfalo/virología , Dengue/patología , Replicación Viral , Adulto , Astrocitos/patología , Encéfalo/metabolismo , Encéfalo/patología , Quimiocina CCL5/metabolismo , Dengue/mortalidad , Dengue/virología , Femenino , Humanos , Interferón gamma/metabolismo , Microglía/patología , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
The role of the local innate immune response in the neuropathogenesis of bovine herpesvirus (BoHV) type 1 and 5 remains largely unknown. This study determined the gene transcriptional expression of relevant bovine cathelicidins, TNFα and IFNß in the nervous system of experimentally-infected cattle during the different stages of BoHV-1 and BoHV-5 infectious cycle. We studied the modulation of bovine myeloid antimicrobial peptide (BMAP) 27 and 28 by alpha-herpesviruses during acute infection of the central nervous system (CNS). However, BMAP28 was the main cathelicidin modulated. BoHV-5 supressed BMAP28 expression mainly in frontal cortex and cervical medulla whereas BoHV-1 slightly induced the expression of cathelicidins in the olfactory and posterior cortex. The differences in the regulation of the innate response are likely related to distinct replication rates of both alpha-herpesviruses in the CNS. During latency and reactivation, BoHV-1 and -5 decreased BMAP28 and BMAP27 expression, accompanied by high levels of TNFα and IFNß transcripts in the posterior brain region and medulla during BoHV reactivation. In terms of cytokines, a remarkably overexpression of IFNß was induced by BoHV-5 (133.8-fold). In trigeminal ganglion (TG) both alpha-herpesviruses induced cathelidicins gene expression at all stages of the infection cycle, while only acute BoHV-5 infection increased TNFα (129-fold) mRNA levels. This study suggests that the pronounced downregulation of BMAP28 in BoHV-5-acutely-infected CNS is due to a decreased immune stimulation during viral infection, favouring its establishment in the CNS with a low replication rate until latency. Thus, cathelicidins, together with IFNß and TNFα, are differentially regulated by BoHV-5 and BoHV-1 infections and this regulation is dependent on the stage of virus infection in the bovine nervous system.
RESUMEN
Abstract Recent reports indicate that besides respiratory and systemic symptoms among coronavirus disease (COVID-19) patients, the disease has a wide spectrum of neurological manifestations (encephalitis, meningitis, myelitis, acute disseminated encephalomyelitis, metabolic and acute hemorrhagic necrotizing encephalopathy, cerebrovascular diseases, Guillain-Barré syndrome, polyneuritis cranialis, dysautonomia, and myopathies). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread from the respiratory system to the central nervous system, using transneuronal and hematogenous mechanisms. Although not every COVID-19 patient will test positive for the virus in the cerebrospinal fluid exam, the appearance of neurological symptoms associated with SARS-CoV-2 infection reveals the importance of understanding the neurologic manifestations and capacity for neural invasion associated with the pathogen. These aspects are relevant for correct diagnosis and treatment, and for the potential development of vaccines. This review highlights the latest evidence of SARS-CoV-2 infection with a focus on neurological involvement and potential neuropathogenesis mechanisms.
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Humanos , Neumonía Viral , Neumonía Viral/diagnóstico , Enfermedades del Sistema Nervioso Central/etiología , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico , Pandemias , Betacoronavirus , Infecciones por Coronavirus , Técnicas de Laboratorio ClínicoRESUMEN
Bovine alphaherpesvirus types 1 (BoHV-1) and 5 (BoHV-5) are closely related alphaherpesviruses. BoHV-5 causes non-suppurative meningoencephalitis in calves. BoHV-1 is associated with several syndromes and, occasionally, can cause encephalitis. Although both viruses are neurotropic and they share similar biological properties, it is unknown why these alphaherpesviruses differ in their ability to cause neurological disease. Neural tissue samples were collected from BoHV-1- and BoHV-5-intranasally inoculated calves during acute infection, latency and reactivation and the levels of cyclins mRNA expression were analyzed by qRT-PCR. Striking differences in the levels of cyclins mRNA were particularly detected in trigeminal ganglion (TG). The expression levels of cyclins in TG during BoHV-5 latency suggest that these viruses utilize different strategies to persist in the host. It is apparent that a relationship between virus loads and cyclin mRNA levels can be established only during acute infection and other factors might be involved in the regulation of cell cycle components during BoHV latency and reactivation. Bovine alphaherpesviruses neuropathogenicity might be influenced by the differential control of cell cycle components by these herpesviruses. This is the first report on BoHV-5 modulation of cyclins expression in neural tissues from its natural host.
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Enfermedades de los Bovinos/patología , Ciclinas/biosíntesis , Encefalitis Viral/veterinaria , Infecciones por Herpesviridae/veterinaria , Herpesvirus Bovino 1/crecimiento & desarrollo , Herpesvirus Bovino 5/crecimiento & desarrollo , Meningoencefalitis/veterinaria , ARN Mensajero/biosíntesis , Animales , Encéfalo/patología , Bovinos , Ciclinas/genética , Encefalitis Viral/patología , Perfilación de la Expresión Génica , Infecciones por Herpesviridae/patología , Meningoencefalitis/virología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Bovine herpesvirus type 1 and type 5 (BoHV-1 and BoHV-5) are two alphaherpesviruses that affect cattle with two different syndromes. While BoHV-1 mainly produces respiratory symptoms, BoHV-5 is highly neuropathogenic and responsible for meningoencephalitis in young cattle. The latency-related (LR) gene, which is not conserved between these two herpesviruses, is the only viral gene abundantly expressed in latently infected neurons. The antiapoptotic action of this gene has been demonstrated during acute infection and reactivation from latency and seems to be mainly mediated by a LR protein (ORF-2) which is truncated in amino acid 51 in the case of BoHV-5. In this work, we show that the BoHV-5 LR gene is less efficient at cell survival and apoptosis inhibition in transient as well as in established neuronal cell lines compared to its BoHV-1 homolog. We hypothesize that the BoHV-5 LR gene may have novel functions that are lacking in the BoHV-1 LR gene and that these differences may contribute to its enhanced neuropathogenesis.
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Infecciones por Herpesviridae/veterinaria , Herpesvirus Bovino 1/genética , Herpesvirus Bovino 5/genética , Rinotraqueítis Infecciosa Bovina/metabolismo , Meningoencefalitis/veterinaria , Proteínas Virales/genética , Latencia del Virus/genética , Animales , Apoptosis/genética , Bovinos , Línea Celular , Expresión Génica , Infecciones por Herpesviridae/patología , Infecciones por Herpesviridae/virología , Herpesvirus Bovino 1/crecimiento & desarrollo , Herpesvirus Bovino 1/metabolismo , Herpesvirus Bovino 5/crecimiento & desarrollo , Herpesvirus Bovino 5/metabolismo , Interacciones Huésped-Patógeno/genética , Rinotraqueítis Infecciosa Bovina/patología , Rinotraqueítis Infecciosa Bovina/virología , Meningoencefalitis/patología , Meningoencefalitis/virología , Neuronas/metabolismo , Neuronas/virología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Virales/metabolismo , Activación ViralRESUMEN
BACKGROUND: Canine distemper virus (CDV), currently termed Canine morbillivirus, is an extremely contagious disease that affects dogs. It is identified as a multiple cell tropism pathogen, and its host range includes a vast array of species. As a member of Mononegavirales, CDV has a negative, single-stranded RNA genome, which encodes eight proteins. MAIN BODY: Regarding the molecular pathogenesis, the hemagglutinin protein (H) plays a crucial role both in the antigenic recognition and the viral interaction with SLAM and nectin-4, the host cells' receptors. These cellular receptors have been studied widely as CDV receptors in vitro in different cellular models. The SLAM receptor is located in lymphoid cells; therefore, the infection of these cells by CDV leads to immunosuppression, the severity of which can lead to variability in the clinical disease with the potential of secondary bacterial infection, up to and including the development of neurological signs in its later stage. CONCLUSION: Improving the understanding of the CDV molecules implicated in the determination of infection, especially the H protein, can help to enhance the biochemical comprehension of the difference between a wide range of CDV variants, their tropism, and different steps in viral infection. The regions of interaction between the viral proteins and the identified host cell receptors have been elucidated to facilitate this understanding. Hence, this review describes the significant molecular and cellular characteristics of CDV that contribute to viral pathogenesis.
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Virus del Moquillo Canino/genética , Virus del Moquillo Canino/patogenicidad , Moquillo/virología , Interacciones Microbiota-Huesped , Tropismo Viral , Animales , Modelos Animales de Enfermedad , Virus del Moquillo Canino/fisiología , Perros , Hemaglutininas Virales/genética , Especificidad del Huésped , Humanos , Ratones , Nectinas/genética , Receptores Virales/genética , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Proteínas Virales/genética , Zoonosis/virologíaRESUMEN
Bovine herpesvirus (BoHV) types 1 and 5 are neuroinvasive. Cases of BoHV-1-induced encephalitis are not as frequent as those caused by BoHV-5. In this study, the capability of BoHV-5 to induce apoptosis in cell cultures and in the trigeminal ganglion during acute infection of experimentally-infected cattle was analyzed. Apoptotic changes in cell cultures agree with the ability of the viral strains to replicate in each cell line. Marked differences were observed between the in vitro induction of apoptosis by BoHV-1Cooper and BoHV-5 97/613 strains. Apoptotic neurons were clearly evident in the trigeminal ganglion of BoHV-1-infected calves. For BoHV-5 a fewer number of positive neurons was observed. There is an association between the magnitude of bovine herpesviruses replication and the induction of apoptosis in trigeminal ganglion. These findings suggest that the induction of apoptosis and the innate immune response orchestrate the final outcome of alpha herpesviruses infection of the bovine nervous system.
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Enfermedades de los Bovinos/virología , Infecciones por Herpesviridae/veterinaria , Herpesvirus Bovino 1/patogenicidad , Herpesvirus Bovino 5/patogenicidad , Neuronas/virología , Ganglio del Trigémino/virología , Animales , Apoptosis , Bovinos , Enfermedades de los Bovinos/inmunología , Enfermedades de los Bovinos/patología , Línea Celular , Células Epiteliales/inmunología , Células Epiteliales/patología , Células Epiteliales/virología , Células HeLa , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/patología , Infecciones por Herpesviridae/virología , Herpesvirus Bovino 1/inmunología , Herpesvirus Bovino 5/inmunología , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Neuronas/inmunología , Neuronas/patología , Especificidad de la Especie , Ganglio del Trigémino/inmunología , Ganglio del Trigémino/patología , Replicación ViralRESUMEN
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.
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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
BACKGROUND: Herpes simplex virus type 1 (HSV-1) cause not only mild symptoms but also blindness and encephalitis. It was previously shown that the immune response against HSV-1 occurs mainly in the trigeminal ganglia (TG) and that Toll-like receptors 2 and 9 (TLR2/9) are important in mediating this response. It was also demonstrated that iNOS (nitric oxide synthase) and interleukin 1 beta (IL-1ß) play an essential role in the defense against HSV-1 infection. Importantly, the present work aimed to identify the primary cells responsible for iNOS and IL-1ß production and search for other important molecules and cells that might or might not depend on TLR2/9 receptors to mediate the immune response against HSV-1. METHODS: C57BL/6 (wild type, WT) and TLR2/9-/- mice were infected by the intranasal route with HSV-1 (1 × 106 p.f.u.). Cells were obtained from the TG and spleen tissues and the profile of immune cells was determined by flow cytometry in infected and mock infected WT and knockout mice. The percentage of cells producing iNOS, IL-1ß, granzyme B and perforin was also determined by flow cytometry. Chemokine monocyte chemoattractant protein-1 (MCP1) was measured by Cytometric Bead Array (CBA) in the TG, spleen and lung. Expression of type I interferons (IFNs), interleukins (IL) 5 and 10, IL-1ß and granzyme B were quantified by real time PCR. RESULTS: The results indicate that dendritic cells (DCs) and monocytes/macrophages (Mo/MÏ) were the main sources of IL-1ß and iNOS, respectively, which, together with type I IFNs, were essential for the immune response against HSV-1. Additionally, we showed that granzyme B produced by CD8+ T and NK lymphocytes and MCP-1 were also important for this immune response. Moreover, our data indicate that the robust production of MCP-1 and granzyme B is either TLR-independent or down regulated by TLRs and occurs in the TG of TLR2/9-/- infected mice. CONCLUSION: Taken together, our data provide strong evidence that the responses mediated by DCs, Mo/MÏ, NK and CD8+ T lymphocytes through IL-1ß, iNOS and granzyme B production, respectively, together with the production of type I IFN early in the infection, are crucial to host defense against HSV-1.
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Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Herpesvirus Humano 1/inmunología , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Ganglio del Trigémino/inmunología , Ganglio del Trigémino/virología , Animales , Citometría de Flujo , Granzimas/metabolismo , Humanos , Interferón Tipo I/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptor Toll-Like 2/deficiencia , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 9/deficiencia , Receptor Toll-Like 9/metabolismoRESUMEN
Dengue virus (DENV) infects approximately 390 million persons every year in more than 100 countries. Reports of neurological complications are more frequently. The objective of this narrative review is to bring up the advances in the dengue neuropathogenesis. DENV can access the nervous system through blood-brain barrier disturbance mediated by cytokine. The blood-cerebrospinal fluid (CSF) barrier seems to be also involved, considering the presence of the virus in the CSF of patients with neurological manifestations. As for neurotropism, several studies showed the presence of RNA and viral antigens in brain tissue and CSF in humans. In murine model, different virus mutations were associated to neurovirulence. Despite the advances in the dengue neuropathogenesis, it is still necessary to determine a more appropriate animal model and increase the number of cases of autopsy. The detection of neurovirulence markers may contribute to establish a prognosis, the disease control and vaccine development.
O vírus da dengue (DENV) infecta anualmente cerca de 390 milhões de indivíduos em mais de 100 países. Complicações neurológicas estão se tornando frequentes. O objetivo desta revisão narrativa é abordar os avanços sobre neuropatogênese na dengue. O DENV invade o sistema nervoso central através do distúrbio da barreira hemato-encefálica, mediado por citocina. A barreira hemato-liquórica (LCR) parece também estar envolvida, considerando a presença do vírus no LCR. Estudos demonstraram RNA e antígenos virais no tecido cerebral e LCR de indivíduos infectados pelo DENV, confirmando o neurotropismo viral. Em modelo murino, diferentes mutações virais foram associadas a neurovirulência. Apesar dos avanços no conhecimento da neuropatogênese da dengue, ainda são necessários a determinação de um modelo animal mais adequado e aumento do número de casos de autopsia. A determinação de marcadores de neurovirulência pode contribuir para o estabelecimento de prognóstico, controle da doença e no desenvolvimento de vacina.
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Animales , Humanos , Enfermedades del Sistema Nervioso Central/virología , Virus del Dengue , Dengue/complicaciones , Sistema Nervioso Central/virología , Modelos Animales de Enfermedad , Virus del Dengue/genética , Dengue/virología , Ilustración Médica , MutaciónRESUMEN
El dengue es la enfermedad viral transmitida por mosquitos más importante en el mundo. Alrededor del 10% de los pacientes con dengue, pueden presentar alteraciones neurológicas durante o después de la infección, asociadas a la replicación viral en el tejido, a la respuesta inmunológica local, a la disfunción endotelial y a signos hemorrágicos en el tejido. En muchos de estos casos se ha detectado virus o anticuerpos en el tejido, sugiriendo la invasión del virus al encéfalo, sin embargo, no siempre es posible hacer esta relación, dando origen a una gran pregunta: ¿son los daños del tejido nervioso producto de una encefalopatía asociada a disfunción extraneural o son debidos a la infección misma del tejido? Como sigue siendo controversial la interpretación de los signos neurológicos durante el dengue, a continuación presentamos algunas generalidades del virus, sus forma clínicas y algunas evidencias clínicas y experimentales que intentan explicar y asociar la neuroinfección y la neuropatogenia por DENV.
Dengue is the most important viral infection transmitted by arthropods in the world. Some studies report that about 10% of dengue or severe dengue patients present neurological symptoms and these signs could be related with nervous system viral replication, immune response and endothelial or metabolic dysfunction in neural or extraneural tissues. These nervous system signs are more frequent in endemic zones and in some patients, viruses or specific antibodies can be detected in the brain, suggesting a direct neural invasion. However, in other cases we cannot establish a direct relationship, begging the question: are the neurological signs and nervous tissue damage secondary to extraneural organ dysfunction or are these changes related to viral replication in the brain? Given the controversy, this review is intended to present some general information on the dengue virus, the clinical characteristics of the disease and current evidence on the neurological manifestations. In addition, we will present experimental evidence to explain the dengue virus neuroinfection and neuropathogenesis.
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Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Dengue , Signos y Síntomas , Virus , Dengue Grave , Encefalitis , Infecciones , Anticuerpos , Sistema NerviosoRESUMEN
Bovine herpesvirus type 5 (BoHV-5) is a major cause of viral meningoencephalitis in cattle. The expression of different viral proteins has been associated with BoHV-5 neuropathogenesis. Among these, gI, gE and US9 have been considered essential for the production of neurological disease in infected animals. To evaluate the role of gI, gE and US9 in neurovirulence, a recombinant from which the respective genes were deleted (BoHV-5 gI-/gE-/US9-) was constructed and inoculated in rabbits of two age groups (four and eight weeks-old). When the recombinant virus was inoculated through the paranasal sinuses of four weeks-old rabbits, neurological disease was observed and death was the outcome in 4 out of 13 (30.7 percent) animals, whereas clinical signs and death were observed in 11/13 (84.6 percent) of rabbits infected with the parental virus. In eight weeks-old rabbits, the BoHV-5 gI-/gE-/US9- did not induce clinically apparent disease and could not be reactivated after dexamethasone administration, whereas wild type BoHV-5 caused disease in 55.5 percent of the animals and was reactivated. These findings reveal that the simultaneous deletion of gI, gE and US9 genes did reduce but did not completely abolish the neurovirulence of BoHV-5 in rabbits, indicating that other viral genes may also play a role in the induction of neurological disease.(AU)
O herpesvírus bovino tipo 5 é uma das principais causas de meningoencefalite viral em bovinos. A expressão de diferentes proteínas virais tem sido associada à neuropatogenia do BoHV-5. Entre estas, a gI, gE e US9 têm sido consideradas essenciais para a indução de sinais neurológicos nos animais infectados. Para avaliar o papel das proteínas gI, gE e US9 na neurovirulência, construiu-se um recombinante no qual os genes que codificam estas proteínas foram deletados, denominado BoHV-5 gI-/gE-/US9-. Este vírus foi inoculado em coelhos de idades diferentes (quatro e oito semanas de idade). Quando o vírus recombinante foi inoculado nos seios paranasais de coelhos de quatro semanas de idade, doença neurológica e morte foram observadas em 4 dos 13 (30,7 por cento) animais, enquanto que sinais clínicos e morte foram observados em 11/13 (84,6 por cento) dos coelhos infectados com o vírus parental. Em coelhos de oito semanas de idade, o BoHV-5 gI-/gE-/US9- não induziu sinais clínicos aparentes e, após tentativa de reativação viral por tratamento com dexametasona, o vírus não foi re-excretado. Por outro lado, o vírus selvagem causou doença clínica em 55,5 por cento dos coelhos e foi re-excretado após tratamento com dexametasona. Estes achados revelam que a deleção simultânea dos genes gI, gE e US9 reduziu mas não aboliu completamente a neurovirulência do BoHV-5 em coelhos, indicando que outros genes virais possam ter papel na indução da doença neurológica.(AU)