RESUMEN
Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.
Asunto(s)
Encéfalo , Senescencia Celular , Herpes Simple , Herpesvirus Humano 1 , Esclerosis Múltiple , Animales , Ratones , Encéfalo/virología , Encéfalo/patología , Encéfalo/metabolismo , Esclerosis Múltiple/virología , Esclerosis Múltiple/patología , Esclerosis Múltiple/metabolismo , Herpesvirus Humano 1/fisiología , Herpesvirus Humano 1/patogenicidad , Herpes Simple/virología , Herpes Simple/patología , Femenino , Ratones Endogámicos C57BL , Encefalomielitis Autoinmune Experimental/virología , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/metabolismo , Fenotipo , Sistema Nervioso Central/virología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Médula Espinal/virología , Médula Espinal/metabolismo , Médula Espinal/patología , Biomarcadores/metabolismo , Encefalitis por Herpes Simple/virología , Encefalitis por Herpes Simple/patología , Encefalitis por Herpes Simple/metabolismoRESUMEN
Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.
Asunto(s)
Encéfalo , Encefalitis por Herpes Simple , Herpesvirus Humano 1 , Proteínas de la Membrana , Internalización del Virus , Animales , Femenino , Humanos , Masculino , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/virología , Encefalitis por Herpes Simple/virología , Encefalitis por Herpes Simple/metabolismo , Herpesvirus Humano 1/patogenicidad , Herpesvirus Humano 1/fisiología , Homocigoto , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nectinas/genética , Nectinas/metabolismo , Neuronas/citología , Neuronas/metabolismo , Neuronas/virología , Células Madre Pluripotentes/citología , Replicación Viral , Preescolar , Adulto Joven , LinajeRESUMEN
BACKGROUND: Herpes simplex encephalitis (HSE) is an important central nervous infection with severe neurological sequelae. The aim of this study was to describe clinical characteristic and outcomes of patients with HSE in Vietnam. METHODS: This was a retrospective study of 66 patients with herpes simplex encephalitis who admitted to the National Hospital for Tropical Diseases, Hanoi, Vietnam from 2018 to 2021. The detection of herpes simplex virus (HSV) in cerebrospinal fluid was made by the real-time PCR assay. We reported the clinical manifestation on admission and evaluated clinical outcomes at the hospital discharge by modified Rankin Scale (mRS). Multivariate logistic regression analysis was used to analyze the independent risk factors of severe outcomes. RESULTS: Of the 66 patients with laboratory confirmed HSE, the median age was 53 years (IQR 38-60) and 44 patients (69.7%) were male. The most common manifestations included fever (100%), followed by the consciousness disorder (95.5%). Other neurological manifestation were seizures (36.4%), memory disorders (31.8%), language disorders (19.7%) and behavioral disorders (13.6%). Conventional magnetic resonance imaging (MRI) showed 93.8% patients with temporal lobe lesions, followed by abnormalities in insula (50%), frontal lobe (34.4%) and 48.4% of patients had bilateral lesions. At discharge, 19 patients (28.8%) completely recovered, 15 patients (22.7%) had mild sequelae, 28 patients (42.4%) had moderate to severe sequelae. Severe neurological sequelae were memory disorders (55.8%), movement disorders (53.5%), language disorders (30.2%). Multivariate logistic regression analysis showed that Glasgow score decrement at admission, seizures, and time duration from onset of symptoms to the start of Acyclovir treatment > 4 days were independent factors associated with severe outcomes in HSE patients. CONCLUSION: Glasgow score decrement, seizures and delay treatment with Acyclovir were associated with the poor outcome of patients with HSE.
Asunto(s)
Encefalitis por Herpes Simple , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Vietnam/epidemiología , Adulto , Encefalitis por Herpes Simple/tratamiento farmacológico , Encefalitis por Herpes Simple/virología , Encefalitis por Herpes Simple/epidemiología , Antivirales/uso terapéutico , Simplexvirus/aislamiento & purificación , Simplexvirus/genética , Factores de Riesgo , Imagen por Resonancia Magnética , Aciclovir/uso terapéutico , Resultado del TratamientoRESUMEN
Viral encephalitis continues to be a significant public health concern. In our previous study, we discovered a lower expression of antiviral factors, such as IFN-ß, STING and IFI16, in the brain tissues of patients with Rasmussen's encephalitis (RE), a rare chronic neurological disorder often occurred in children, characterized by unihemispheric brain atrophy. Furthermore, a higher cumulative viral score of human herpes viruses (HHVs) was also found to have a significant positive correlation with the unihemispheric atrophy in RE. Type I IFNs (IFN-I) signaling is essential for innate anti-infection response by binding to IFN-α/ß receptor (IFNAR). In this study, we infected WT mice and IFNAR-deficient A6 mice with herpes simplex virus 1 (HSV-1) via periocular injection to investigate the relationship between IFN-I signaling and HHVs-induced brain lesions. While all mice exhibited typical viral encephalitis lesions in their brains, HSV-induced epilepsy was only observed in A6 mice. The gene expression matrix, functional enrichment analysis and protein-protein interaction network revealed four gene models that were positively related with HSV-induced epilepsy. Additionally, ten key genes with the highest scores were identified. Taken together, these findings indicate that intact IFN-I signaling can effectively limit HHVs induced neural symptoms and brain lesions, thereby confirming the positive correlation between IFN-I signaling repression and brain atrophy in RE and other HHVs encephalitis.
Asunto(s)
Epilepsia , Herpes Simple , Herpesvirus Humano 1 , Interferón Tipo I , Transducción de Señal , Animales , Femenino , Ratones , Encéfalo/patología , Encéfalo/virología , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/virología , Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/patología , Epilepsia/virología , Epilepsia/patología , Herpes Simple/virología , Herpes Simple/patología , Herpes Simple/inmunología , Herpesvirus Humano 1/patogenicidad , Herpesvirus Humano 1/inmunología , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Mapas de Interacción de Proteínas , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/deficienciaAsunto(s)
Astrocitos/inmunología , Encefalitis por Herpes Simple/inmunología , Interferón Tipo I/inmunología , Animales , Astrocitos/virología , Encéfalo/inmunología , Encéfalo/virología , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Estimación de Kaplan-Meier , Ratones , Ratones Noqueados , Microglía/inmunología , Microglía/virología , Receptor de Interferón alfa y beta/deficiencia , Receptor de Interferón alfa y beta/inmunología , Transducción de Señal , Carga ViralRESUMEN
Herpes simplex virus type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE), a condition characterized by acute inflammation and viral replication in the brain. Host genetics contribute to HSE onset, including monogenic defects in type I interferon signaling in cases of childhood HSE. Mouse models suggest a further contribution of immune cell-mediated inflammation to HSE pathogenesis. We have previously described a truncating mutation in the c-Rel transcription factor (RelC307X) that drives lethal HSE in 60% of HSV-1-infected RelC307X mice. In this study, we combined dual host-virus RNA sequencing with flow cytometry to explore cell populations and mechanisms involved in RelC307X-driven HSE. At day 5 postinfection, prior to HSE clinical symptom onset, elevated HSV-1 transcription was detected together with augmented host interferon-stimulated and inflammatory gene expression in the brainstems of high-responding RelC307X mice, predictive of HSE development. This early induction of host gene expression preceded pathological infiltration of myeloid and T cells in RelC307X mice at HSE onset by day 7. Thus, we establish c-Rel as an early regulator of viral and host responses during mouse HSE. These data further highlight the importance of achieving a balanced immune response and avoiding excess interferon-driven inflammation to promote HSE resistance.
Asunto(s)
Encefalitis por Herpes Simple/metabolismo , Interferón Tipo I/metabolismo , Proteínas Proto-Oncogénicas c-rel/metabolismo , Animales , Encefalitis por Herpes Simple/virología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Proteínas Proto-Oncogénicas c-rel/genética , Transducción de Señal , Simplexvirus/genética , Simplexvirus/patogenicidad , Simplexvirus/fisiología , Linfocitos T/metabolismo , Linfocitos T/virologíaRESUMEN
Herpes simplex virus 1 (HSV-1) is responsible for herpes simplex virus encephalitis (HSE), associated with a 70% mortality rate in the absence of treatment. Despite intravenous treatment with acyclovir, mortality remains significant, highlighting the need for new anti-herpetic agents. Herein, we describe a novel neurovirulent recombinant HSV-1 (rHSV-1), expressing the fluorescent tdTomato and Gaussia luciferase (Gluc) enzyme, generated by the Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) (CRISPR-Cas9) system. The Gluc activity measured in the cell culture supernatant was correlated (P = 0.0001) with infectious particles, allowing in vitro monitoring of viral replication kinetics. A significant correlation was also found between brain viral titers and Gluc activity in plasma (R2 = 0.8510, P < 0.0001) collected from BALB/c mice infected intranasally with rHSV-1. Furthermore, evaluation of valacyclovir (VACV) treatment of HSE could also be performed by analyzing Gluc activity in mouse plasma samples. Finally, it was also possible to study rHSV-1 dissemination and additionally to estimate brain viral titers by in vivo imaging system (IVIS). The new rHSV-1 with reporter proteins is not only as a powerful tool for in vitro and in vivo antiviral screening, but can also be used for studying different aspects of HSE pathogenesis.
Asunto(s)
Encefalitis por Herpes Simple/fisiopatología , Herpesvirus Humano 1/aislamiento & purificación , Animales , Antivirales/uso terapéutico , Secuencia de Bases , Barrera Hematoencefálica , Encéfalo/virología , Chlorocebus aethiops , Encefalitis por Herpes Simple/tratamiento farmacológico , Encefalitis por Herpes Simple/virología , Genes Reporteros , Genes Virales , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/fisiología , Luminiscencia , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena de la Polimerasa Multiplex/métodos , Valaciclovir/uso terapéutico , Células Vero , Carga Viral , Replicación Viral/genéticaRESUMEN
BACKGROUND: Herpes simplex virus encephalitis (HSE) is an acute central nervous system infectious disease caused by herpes simplex virus (HSV). Currently, there is no effective treatment for HSE infection, which produces many pro-inflammatory factors. Kaempferol-3-O-rhamnoside (K-3-rh) is a plant flavonoid. This study was investigated the anti-inflammatory effect of K-3-rh on encephalitis induced by HSV-1. METHODS: HSV-1 was co-cultured with VERO cells. Cells were divided into four groups, including the control group, virus group, K-3-rh group, Astragalus polysaccharide (APS) group and dexamethasone group. Flow cytometry were utilized to determine cell apoptosis, respectively. Proteins and mRNAs were estimated by western blot and qRT-PCR, respectively. RESULTS: After viral infection, the cytokines were significantly increased. After K-3-rh intervention, the expression of tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1ß), and nitric oxide (NO) in microglia were reduced contrast with those in the virus group, and the expression of interleukin-10 (IL-10) did not change. After viral infection, the apoptotic rate increased significantly, and K-3-rh could inhibit viral-induced apoptosis in the microglial cell line. The induction of microglia apoptosis was achieved by cytochrome c and caspase-9-mediated mitochondrial pathway. Also, the pathological changes of brain tissue in mice of each drug intervention group were alleviated. CONCLUSIONS: In conclusion, K-3-rh had the potential to reduce HSV-1-induced brain injury by reducing the secretion of microglial pro-inflammatory factors, inducing apoptosis of microglia cells, and through cytochrome C and caspase-3 pathway.
Asunto(s)
Encefalitis por Herpes Simple/tratamiento farmacológico , Glicósidos/farmacología , Herpesvirus Humano 1/inmunología , Quempferoles/farmacología , Microglía/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Caspasa 3/metabolismo , Línea Celular , Chlorocebus aethiops , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/patología , Encefalitis por Herpes Simple/virología , Glicósidos/uso terapéutico , Humanos , Quempferoles/uso terapéutico , Ratones , Microglía/inmunología , Microglía/patología , Microglía/virología , Células VeroRESUMEN
To explore the differently expressed cytokines and chemokines to understand the pathways that lead to herpes simplex encephalitis (HSE). Mice in the experimental group were inoculated intracranially with HSV-1. A high-throughput cytokine chip assay was employed to assess the expression of cytokines/chemokines in the mice brain. GO, KEGG, and PPIs analyses were used to investigate the biological process (BP), pathways and interaction network of the differently expressed proteins (DEPs) in HSE. 13 DEPs and various proteins-related signal pathways were identified in HSE, including three new factors (IL-1α, MIP-1γ, and sTNF RI). The proteins were mainly implicated in leukocyte activation and chemotaxis. Additionally, the DEPs constituted a pivotal protein interaction network where IL-6 might be a mediator. 13 DEPs and a series of related signal pathways were associated with the pathophysiological mechanisms responsible for HSE. IL-6 might be a key mediator in the inflammatory responses to the disease.
Asunto(s)
Encéfalo/patología , Citocinas/metabolismo , Encefalitis por Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Animales , Encéfalo/inmunología , Encéfalo/virología , Chlorocebus aethiops , Citocinas/análisis , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/patología , Encefalitis por Herpes Simple/virología , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Mapas de Interacción de Proteínas/genética , Mapas de Interacción de Proteínas/inmunología , Células VeroRESUMEN
Herpes simplex virus encephalitis (HSE) is the most common sporadic fatal encephalitis. Although timely administered acyclovir treatment decreases mortality, neuropsychiatric sequelae is still common among survivors. Magnetic resonance imaging is frequently utilized for the diagnosis of HSE, which typically involves temporal lobe(s) and can be mixed with brain tumors involving the same area. Here, we report a case of HSE, who received acyclovir with a delay of 90 days because of presumptive tumor diagnosis and survived with minimal sequelae.
Asunto(s)
Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Encefalitis por Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Lóbulo Temporal/efectos de los fármacos , Adulto , Diagnóstico Tardío , Encefalitis por Herpes Simple/diagnóstico por imagen , Encefalitis por Herpes Simple/patología , Encefalitis por Herpes Simple/virología , Femenino , Herpesvirus Humano 1/crecimiento & desarrollo , Herpesvirus Humano 1/patogenicidad , Humanos , Imagen por Resonancia Magnética , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/patología , Lóbulo Temporal/virología , Resultado del TratamientoRESUMEN
Identification of the complete set of translated genes of viruses is important to understand viral replication and pathogenesis as well as for therapeutic approaches to control viral infection. Here, we use chemical proteomics, integrating bio-orthogonal non-canonical amino acid tagging and high-resolution mass spectrometry, to characterize the newly synthesized herpes simplex virus 1 (HSV-1) proteome in infected cells. In these infected cells, host cellular protein synthesis is shut-off, increasing the chance to preferentially detect viral proteomes. We identify nine previously cryptic orphan protein coding sequences whose translated products are expressed in HSV-1-infected cells. Functional characterization of one identified protein, designated piUL49, shows that it is critical for HSV-1 neurovirulence in vivo by regulating the activity of virally encoded dUTPase, a key enzyme that maintains accurate DNA replication. Our results demonstrate that cryptic orphan protein coding genes of HSV-1, and probably other large DNA viruses, remain to be identified.
Asunto(s)
Encefalitis por Herpes Simple/virología , Herpesvirus Humano 1/patogenicidad , Pirofosfatasas/metabolismo , Proteínas Virales/metabolismo , Factores de Virulencia/metabolismo , Animales , Encéfalo/patología , Encéfalo/virología , Chlorocebus aethiops , Replicación del ADN , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/patología , Femenino , Genes Virales/genética , Células HEK293 , Células HeLa , Herpesvirus Humano 1/genética , Humanos , Ratones , Biosíntesis de Proteínas , Proteómica/métodos , Células Vero , Proteínas Virales/genética , Factores de Virulencia/genética , Replicación ViralRESUMEN
In January 2008, a 59-year-old man with a history of diabetes mellitus was admitted to our hospital with herpes simplex virus (HSV) encephalitis of his right temporal lobe, which was diagnosed by PCR testing of his cerebrospinal fluid (CSF). He was treated with intravenous acyclovir for three weeks and made a full recovery. On discharge, his CSF was negative for HSV on PCR testing. Seven years later, in March 2015, the man was readmitted to our hospital with fever, disorientation, and nominal dysphasia. Diffusion-weighted MRI of his head revealed a high-intensity area in his left temporal lobe. Testing of his CSF revealed a moderately increased monocyte count and HSV on PCR testing, so he was diagnosed with recurrent HSV encephalitis. He was treated with intravenous acyclovir for three weeks. On discharge, his CSF was negative for HSV on PCR testing, but he had mild residual amnesia. There have been few reports of HSV encephalitis with viral reactivation recurring after a long remission period in adults. This case illustrates the need for prolonged follow up of individuals with HSV encephalitis in order to detect recurrences.
Asunto(s)
Aciclovir/uso terapéutico , Encefalitis por Herpes Simple/diagnóstico , Encefalitis por Herpes Simple/tratamiento farmacológico , Anciano , Líquido Cefalorraquídeo/virología , Encefalitis por Herpes Simple/virología , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Recurrencia , Simplexvirus/aislamiento & purificación , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Febrile neonates and young infants presenting with seizure require immediate evaluation and treatment. Herein we experienced two young infants with parechovirus-A3 (PeV-A3) encephalitis, initially presented with focal seizure suspecting herpes simplex virus (HSV) encephalitis. CASES: We have experienced 2 infantile cases, initially presented with focal seizure. At presentation, HSV encephalitis was strongly suspected and empiric acyclovir therapy was started; however, serum and/or cerebrospinal fluid (CSF) PCR for HSV were negative. Instead, serum and/or CSF PCR for parechovirus-A was positive. PeV-A3 infection was confirmed by genetic sequence analyses. Both cases required multiple anticonvulsant therapy and intensive care for intractable seizure. Diffusion-weighted imaging of brain magnetic resonance imaging (MRI) showed distinct findings; high-intensity lesions in the gray matter of parietal and occipital lobes in Case 1, and bilateral decreased diffusion of the deep white matter and corpus callosum in Case 2. We have followed two cases more than four years; Case 1 developed epilepsy, has been on an anticonvulsant to control her seizure. Case 2 has significant neurodevelopmental delay, unable to stand or communicate with language. CONCLUSIONS: PeV-A3 encephalitis needs to be in differential diagnosis when neonates and young infants present with focal seizure, mimicking HSV encephalitis. Special attention may be necessary in patients with PeV-A3 encephalitis given it could present with intractable seizure with high morbidity in a long-term.
Asunto(s)
Encefalitis por Herpes Simple/diagnóstico , Encefalitis Viral/diagnóstico , Parechovirus/aislamiento & purificación , Infecciones por Picornaviridae/diagnóstico , Convulsiones/virología , Encéfalo/diagnóstico por imagen , ADN Viral/aislamiento & purificación , Diagnóstico Diferencial , Imagen de Difusión por Resonancia Magnética , Encefalitis por Herpes Simple/virología , Encefalitis Viral/líquido cefalorraquídeo , Encefalitis Viral/complicaciones , Encefalitis Viral/virología , Epilepsia/tratamiento farmacológico , Epilepsia/virología , Femenino , Humanos , Lactante , Recien Nacido Prematuro , Masculino , Trastornos del Neurodesarrollo/virología , Parechovirus/genética , Infecciones por Picornaviridae/líquido cefalorraquídeo , Infecciones por Picornaviridae/complicaciones , Infecciones por Picornaviridae/virología , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , ARN Viral/aislamiento & purificación , Convulsiones/sangre , Convulsiones/líquido cefalorraquídeo , Convulsiones/diagnóstico , Simplexvirus/genética , Simplexvirus/aislamiento & purificaciónRESUMEN
Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Over the last 15 years, human genetic and immunological studies have provided proof-of-principle that childhood HSE can result from inborn errors of central nervous system (CNS)-specific, cell-intrinsic immunity to HSV-1. HSE-causing mutations of eight genes disrupt known (TLR3-dependent IFN-α/ß immunity) and novel (dependent on DBR1 or snoRNA31) antiviral mechanisms. Monogenic inborn errors confer susceptibility to forebrain (TLR3-IFN or snoRNA31) or brainstem (DBR1) HSE. Most of these disorders display incomplete clinical penetrance, with the possible exception of DBR1 deficiency. They account for a small, but non-negligible proportion of cases (about 7%). These findings pave the way for the gradual definition of the genetic and immunological architecture of childhood HSE, with both biological and clinical implications.
Asunto(s)
Enfermedades del Sistema Nervioso Central/genética , Encefalitis por Herpes Simple/genética , Predisposición Genética a la Enfermedad , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Interacciones Huésped-Patógeno/genética , Inmunidad Celular/inmunología , Enfermedades del Sistema Nervioso Central/epidemiología , Enfermedades del Sistema Nervioso Central/inmunología , Enfermedades del Sistema Nervioso Central/virología , Niño , Encefalitis por Herpes Simple/epidemiología , Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/virología , Herpes Simple/complicaciones , Herpes Simple/virología , Herpesvirus Humano 1/patogenicidad , Interacciones Huésped-Patógeno/inmunología , Humanos , MutaciónRESUMEN
BACKGROUND: Herpes zoster ophthalmicus occurs primarily in elderly or immunocompromised individuals after reactivation of varicella zoster virus (VZV). Recurrences of zoster ophthalmicus are uncommon because the reactivation efficiently boosts anti-VZV immunity. A 28-year-old female presented to our clinic with a history of multiple recurrences of zoster ophthalmicus. METHODS: Whole-exome sequencing (WES), analyses of VZV T-cell immunity, and pathogen recognition receptor function in primary antigen-presenting cells (APCs) and fibroblasts were performed. RESULTS: Normal VZV-specific T-cell immunity and antibody response were detected. Whole-exome sequencing identified a heterozygous nonsynonymous variant (c.2324C > T) in the Toll-like receptor 3 (TLR3) gene resulting in formation of a premature stop-codon. This alteration could potentially undermine TLR3 signaling in a dominant-negative fashion. Therefore, we investigated TLR3 signaling responses in APCs and fibroblasts from the patient. The APCs responded efficiently to stimulation with TLR3 ligands, whereas the responses from the fibroblasts were compromised. CONCLUSIONS: We report a novel TLR3 variant associated with recurrent zoster ophthalmicus. Toll-like receptor 3 responses that were unaffected in APCs but diminished in fibroblasts are in line with previous reports linking TLR3 deficiency with herpes simplex virus encephalitis. Mechanisms involving compromised viral sensing in infected cells may thus be central to the described immunodeficiency.
Asunto(s)
Herpes Zóster Oftálmico/virología , Herpesvirus Humano 3/patogenicidad , Mutación/genética , Receptor Toll-Like 3/genética , Adulto , Encefalitis por Herpes Simple/genética , Encefalitis por Herpes Simple/virología , Femenino , Fibroblastos/virología , Herpes Zóster/genética , Herpes Zóster/virología , Herpes Zóster Oftálmico/genética , Humanos , Huésped Inmunocomprometido/genéticaRESUMEN
Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.
Asunto(s)
Encefalitis por Herpes Simple/genética , Herpesvirus Humano 1/genética , Neuronas/inmunología , ARN Nucleolar Pequeño/genética , Adulto , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/virología , Preescolar , Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/patología , Encefalitis por Herpes Simple/virología , Femenino , Predisposición Genética a la Enfermedad , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/patogenicidad , Humanos , Inmunidad/genética , Lactante , Masculino , Metagenoma/genética , Metagenoma/inmunología , Persona de Mediana Edad , Neuronas/virología , ARN Nucleolar Pequeño/inmunologíaRESUMEN
Microglia, as brain-resident macrophages, are the first line of defense against brain invading pathogens. Further, their dysfunction has been recognized to be closely associated with mounting CNS diseases. Of note, chronic HSV-1 infection leads to the persistent activation of microglia, which elicit a comprehensive response by generating certain factors with neurotoxic and neuroprotective effects. CNS infection with HSV-1 results in herpes simplex encephalitis and herpes simplex keratitis. Microglial immune response plays a crucial role in the development of these diseases. Moreover, HSV-1 infection is strongly associated with several CNS diseases, especially Alzheimer's disease and schizophrenia. These CNS diseases can be effectively ameliorated by eliciting an appropriate immune response, such as inhibition of microglial proliferation and activation. Therefore, it is crucial to reassess the positive and negative roles of microglia in HSV-1 CNS infection for a more comprehensive and detailed understanding of the relationship between microglia and CNS diseases. Hence, the present review focuses on the dual roles of microglia in mediating HSV-1 CNS infection, as well as on the strategy of targeting microglia to ameliorate CNS diseases. Further research in this field can help comprehensively elucidate the dual role of the microglial immune response in HSV-1 CNS infection, providing a theoretical basis for identifying therapeutic targets against overactive microglia in CNS diseases and HSV-1 infection.
Asunto(s)
Encefalitis por Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Microglía/inmunología , Animales , Encefalitis por Herpes Simple/inmunología , Herpesvirus Humano 1/genética , Humanos , Microglía/virologíaAsunto(s)
Encefalitis por Herpes Simple/diagnóstico , Herpesvirus Humano 2/aislamiento & purificación , Meningitis Viral/diagnóstico , Reacción en Cadena de la Polimerasa Multiplex/métodos , Adulto , Algoritmos , Encefalitis por Herpes Simple/líquido cefalorraquídeo , Encefalitis por Herpes Simple/virología , Humanos , Masculino , Meningitis Viral/líquido cefalorraquídeo , Meningitis Viral/virologíaRESUMEN
Herpes simplex virus 1 (HSV-1) is a predominant cause of herpes simplex encephalitis (HSE), leading to a high mortality rate and severe neurological sequelae worldwide. HSE is typically accompanied by the blood-brain barrier (BBB) disruption, but the underlying mechanisms are unclear. To explore the disruption mechanisms of the BBB, quantitative analysis of the cellular proteome was carried out to investigate the proteomic changes that occur after infection. In this study, bEnd.3 cells were infected with HSV-1, followed by liquid chromatography-tandem mass spectrometry. A total of 6761 proteins were identified in three independent mass spectrometry analyses. Compared to the uninfected cells, 386 and 293 differentially expressed proteins were markedly upregulated or downregulated, respectively. Bioinformatic analysis showed that the activator protein-1 factor, including Fos, Jun, and ATF family proteins and cell adhesion molecules were significantly changed. Further validation of the changes observed for these proteins was carried out by western blotting and quantitative real-time PCR. Transendothelial electrical resistance (TEER) studies were performed to explore the effects of ATF3, Fra1, or JunB overexpression on the function of bEnd.3 cells. Characterization of the differential expression of these proteins in bEnd.3 cells will facilitate further exploration of BBB disruption upon HSV-1 infection.
Asunto(s)
Factor de Transcripción Activador 3/genética , Encefalitis por Herpes Simple/genética , Células Endoteliales/metabolismo , Herpesvirus Humano 1/fisiología , Proteínas Proto-Oncogénicas c-fos/genética , Factores de Transcripción/genética , Factor de Transcripción Activador 3/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/virología , Encéfalo/metabolismo , Encéfalo/virología , Línea Celular , Encefalitis por Herpes Simple/metabolismo , Encefalitis por Herpes Simple/virología , Células Endoteliales/virología , Regulación de la Expresión Génica , Ontología de Genes , Herpesvirus Humano 1/patogenicidad , Interacciones Huésped-Patógeno/genética , Humanos , Ratones , Modelos Biológicos , Anotación de Secuencia Molecular , Proteoma/clasificación , Proteoma/genética , Proteoma/metabolismo , Proteómica/métodos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Factores de Transcripción/metabolismo , Replicación ViralRESUMEN
The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4+ and CD8+ T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag-/-, B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections.