RESUMEN
The type I interferon (IFN) response is the body's typical immune defense against viruses. Previous studies linked high expression of genes encoding type I IFNs in the brain's choroid plexus to cognitive decline under virus-free conditions in aging and neurodegeneration. Multiple reports have documented persisting cognitive symptoms following recovery from COVID-19. Cumulative evidence shows that the choroid plexus is one of the brain regions most vulnerable to infection with the coronavirus SARS-CoV-2, and manifests increased expression of genes encoding type I IFNs even in the absence of viral traces within the brain. In this Perspective, we propose that the type I IFN defensive immune response to SARS-CoV-2 infection in the choroid plexus poses a risk to cognitive function if not resolved in a timely manner.
Asunto(s)
COVID-19 , Interferón Tipo I , Humanos , COVID-19/metabolismo , Interferón Tipo I/metabolismo , SARS-CoV-2/fisiología , Plexo Coroideo/metabolismo , Cognición , Antivirales/metabolismo , Interferones/metabolismoRESUMEN
For decades, it was commonly accepted that the brain is secluded from peripheral immune activity and is self-sufficient for its maintenance and repair. This simplistic perception was based on the presence of resident immune cells, the microglia, and barrier systems within the brain, and the assumption that the central nervous system (CNS) lacks lymphatic drainage. This view was revised with the discoveries that higher functions of the CNS, homeostasis and repair are supported by peripheral innate and adaptive immune cells. The findings of bone marrow-derived immune cells in specialized niches, and the renewed observation that a lymphatic drainage system exists within the brain, further contributed to this revised model. In this Review, we describe the immune niches within the brain, the contribution of professional immune cells to brain functions, the bidirectional relationships between the CNS and the immune system and the relevance of immune components to brain aging and neurodegenerative diseases.
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Encéfalo/inmunología , Inmunidad/fisiología , Microglía/inmunología , Enfermedades Neurodegenerativas/inmunología , Envejecimiento/inmunología , Barrera Hematoencefálica/inmunología , Células de la Médula Ósea/inmunología , Líquido Cefalorraquídeo/citología , Líquido Cefalorraquídeo/inmunología , Humanos , Subgrupos Linfocitarios/inmunología , Macrófagos/inmunologíaRESUMEN
A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body's intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs). Combining data from transcriptional analysis of DAM at single-cell level and from human genome-wide association studies (GWASs), we discuss potential function of different DAM pathways in the diseased brain and outline how manipulating DAM may create new therapeutic opportunities.
Asunto(s)
Microglía/metabolismo , Enfermedades Neurodegenerativas/patología , Animales , Sistema Nervioso Central/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/metabolismo , Receptores Inmunológicos/metabolismo , Transducción de SeñalRESUMEN
Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aß particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)-/- Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Microglía/patología , Fagocitos/patología , Enfermedad de Alzheimer/genética , Animales , Humanos , Ratones , Ratones Transgénicos , Microglía/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/patología , Fagocitos/metabolismo , Receptores Inmunológicos/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula IndividualRESUMEN
Genetic screens have transformed our ability to interrogate cellular factor requirements for viral infections1,2, but most current approaches are limited in their sensitivity, biased towards early stages of infection and provide only simplistic phenotypic information that is often based on survival of infected cells2-4. Here, by engineering human cytomegalovirus to express single guide RNA libraries directly from the viral genome, we developed virus-encoded CRISPR-based direct readout screening (VECOS), a sensitive, versatile, viral-centric approach that enables profiling of different stages of viral infection in a pooled format. Using this approach, we identified hundreds of host dependency and restriction factors and quantified their direct effects on viral genome replication, viral particle secretion and infectiousness of secreted particles, providing a multi-dimensional perspective on virus-host interactions. These high-resolution measurements reveal that perturbations altering late stages in the life cycle of human cytomegalovirus (HCMV) mostly regulate viral particle quality rather than quantity, establishing correct virion assembly as a critical stage that is heavily reliant on virus-host interactions. Overall, VECOS facilitates systematic high-resolution dissection of the role of human proteins during the infection cycle, providing a roadmap for in-depth study of host-herpesvirus interactions.
Asunto(s)
Sistemas CRISPR-Cas , Infecciones por Citomegalovirus , Citomegalovirus , Interacciones Huésped-Patógeno , ARN Guía de Sistemas CRISPR-Cas , Replicación Viral , Humanos , Línea Celular , Sistemas CRISPR-Cas/genética , Citomegalovirus/genética , Citomegalovirus/fisiología , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/virología , Genoma Viral/genética , Interacciones Huésped-Patógeno/genética , ARN Guía de Sistemas CRISPR-Cas/genética , ARN Guía de Sistemas CRISPR-Cas/metabolismo , Virión/genética , Virión/metabolismo , Ensamble de Virus/genética , Liberación del Virus/genética , Replicación Viral/genéticaRESUMEN
It is increasingly clear that the central nervous system (CNS) relies significantly on both adaptive and innate immune cells for its repair and lifelong maintenance. These interactions hold profound implications for brain aging and neurodegeneration. Recent work by Smyth et al. describes newfound anatomical connections between the brain and dura mater, which they named the arachnoid cuff exit points.
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Encéfalo , Sistema Inmunológico , Humanos , Encéfalo/inmunología , Animales , Sistema Inmunológico/inmunología , Inmunidad Innata , Duramadre/inmunología , Envejecimiento/inmunología , Inmunidad AdaptativaRESUMEN
The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-191. Coronaviruses have developed a variety of mechanisms to repress host mRNA translation to allow the translation of viral mRNA, and concomitantly block the cellular innate immune response2,3. Although several different proteins of SARS-CoV-2 have previously been implicated in shutting off host expression4-7, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here we combine RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA to comprehensively define the mechanisms that are used by SARS-CoV-2 to shut off cellular protein synthesis. We show that infection leads to a global reduction in translation, but that viral transcripts are not preferentially translated. Instead, we find that infection leads to the accelerated degradation of cytosolic cellular mRNAs, which facilitates viral takeover of the mRNA pool in infected cells. We reveal that the translation of transcripts that are induced in response to infection (including innate immune genes) is impaired. We demonstrate this impairment is probably mediated by inhibition of nuclear mRNA export, which prevents newly transcribed cellular mRNA from accessing ribosomes. Overall, our results uncover a multipronged strategy that is used by SARS-CoV-2 to take over the translation machinery and to suppress host defences.
Asunto(s)
COVID-19/metabolismo , COVID-19/virología , Interacciones Huésped-Patógeno , Biosíntesis de Proteínas , SARS-CoV-2/patogenicidad , Regiones no Traducidas 5'/genética , COVID-19/genética , COVID-19/inmunología , Línea Celular , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata/genética , Biosíntesis de Proteínas/genética , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/metabolismo , Ribosomas/metabolismo , Proteínas no Estructurales Virales/metabolismoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic1. To understand the pathogenicity and antigenic potential of SARS-CoV-2 and to develop therapeutic tools, it is essential to profile the full repertoire of its expressed proteins. The current map of SARS-CoV-2 coding capacity is based on computational predictions and relies on homology with other coronaviruses. As the protein complement varies among coronaviruses, especially in regard to the variety of accessory proteins, it is crucial to characterize the specific range of SARS-CoV-2 proteins in an unbiased and open-ended manner. Here, using a suite of ribosome-profiling techniques2-4, we present a high-resolution map of coding regions in the SARS-CoV-2 genome, which enables us to accurately quantify the expression of canonical viral open reading frames (ORFs) and to identify 23 unannotated viral ORFs. These ORFs include upstream ORFs that are likely to have a regulatory role, several in-frame internal ORFs within existing ORFs, resulting in N-terminally truncated products, as well as internal out-of-frame ORFs, which generate novel polypeptides. We further show that viral mRNAs are not translated more efficiently than host mRNAs; instead, virus translation dominates host translation because of the high levels of viral transcripts. Our work provides a resource that will form the basis of future functional studies.
Asunto(s)
Perfilación de la Expresión Génica , Genoma Viral/genética , Sistemas de Lectura Abierta/genética , Biosíntesis de Proteínas , SARS-CoV-2/genética , Proteínas Virales/biosíntesis , Proteínas Virales/genética , Animales , Línea Celular , Humanos , Anotación de Secuencia Molecular , Péptidos/genética , Péptidos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/genética , ARN Viral/metabolismo , Ribosomas/metabolismo , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Proteínas Virales/metabolismoRESUMEN
Hemorrhagic stroke, primarily caused by rupture of blood vessels in the brain, is a leading cause of death and disability in adults. In this issue of Immunity, Liu et al. (2016) demonstrate that repair of cerebrovascular ruptures can be directly mediated by myeloid cells.
Asunto(s)
Encéfalo/irrigación sanguínea , Células Mieloides , HumanosRESUMEN
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.
Asunto(s)
Esclerosis Amiotrófica Lateral/microbiología , Esclerosis Amiotrófica Lateral/fisiopatología , Microbioma Gastrointestinal/fisiología , Niacinamida/metabolismo , Akkermansia , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Antibacterianos/farmacología , Modelos Animales de Enfermedad , Disbiosis , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Vida Libre de Gérmenes , Humanos , Longevidad , Masculino , Ratones , Ratones Transgénicos , Niacinamida/biosíntesis , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Tasa de Supervivencia , Simbiosis/efectos de los fármacos , Verrucomicrobia/metabolismo , Verrucomicrobia/fisiologíaRESUMEN
The rapid transcriptional response to the transcription factor, glucocorticoid receptor (GR), including gene activation or repression, is mediated by the spatial association of genes with multiple GR binding sites (GBSs) over large genomic distances. However, only a minority of the GBSs have independent GR-mediated activating capacity, and GBSs with independent repressive activity were rarely reported. To understand the positive and negative effects of GR we mapped the regulatory environment of its gene targets. We show that the chromatin interaction networks of GR-activated and repressed genes are spatially separated and vary in the features and configuration of their GBS and other non-GBS regulatory elements. The convergence of the KLF4 pathway in GR-activated domains and the STAT6 pathway in GR-repressed domains, impose opposite transcriptional effects to GR, independent of hormone application. Moreover, the ROR and Rev-erb transcription factors serve as positive and negative regulators, respectively, of GR-mediated gene activation. We found that the spatial crosstalk between GBSs and non-GBSs provides a physical platform for sequestering the Ep300 co-activator from non-GR regulatory loci in both GR-activated and -repressed gene compartments. While this allows rapid gene repression, Ep300 recruitment to GBSs is productive specifically in the activated compartments, thus providing the basis for gene induction.
Asunto(s)
Proteína p300 Asociada a E1A , Regulación de la Expresión Génica , Receptores de Glucocorticoides , Receptores de Glucocorticoides/genética , Activación Transcripcional/genética , Línea Celular Tumoral , Humanos , Animales , Ratones , Proteína p300 Asociada a E1A/metabolismoRESUMEN
Reactivation of human cytomegalovirus (HCMV) from latency is a major health consideration for recipients of stem-cell and solid organ transplantations. With over 200,000 transplants taking place globally per annum, virus reactivation can occur in more than 50% of cases leading to loss of grafts as well as serious morbidity and even mortality. Here, we present the most extensive screening to date of epigenetic inhibitors on HCMV latently infected cells and find that histone deacetylase inhibitors (HDACis) and bromodomain inhibitors are broadly effective at inducing virus immediate early gene expression. However, while HDACis, such as myeloid-selective CHR-4487, lead to production of infectious virions, inhibitors of bromodomain (BRD) and extraterminal proteins (I-BETs), including GSK726, restrict full reactivation. Mechanistically, we show that BET proteins (BRDs) are pivotally connected to regulation of HCMV latency and reactivation. Through BRD4 interaction, the transcriptional activator complex P-TEFb (CDK9/CycT1) is sequestered by repressive complexes during HCMV latency. Consequently, I-BETs allow release of P-TEFb and subsequent recruitment to promoters via the superelongation complex (SEC), inducing transcription of HCMV lytic genes encoding immunogenic antigens from otherwise latently infected cells. Surprisingly, this occurs without inducing many viral immunoevasins and, importantly, while also restricting viral DNA replication and full HCMV reactivation. Therefore, this pattern of HCMV transcriptional dysregulation allows effective cytotoxic immune targeting and killing of latently infected cells, thus reducing the latent virus genome load. This approach could be safely used to pre-emptively purge the virus latent reservoir prior to transplantation, thereby reducing HCMV reactivation-related morbidity and mortality.
Asunto(s)
Proteínas de Ciclo Celular/genética , Citomegalovirus/inmunología , ADN Viral/genética , Epigénesis Genética , Histona Desacetilasas/genética , Factor B de Elongación Transcripcional Positiva/genética , Factores de Transcripción/genética , Azepinas/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Benzodiazepinas/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/inmunología , Ciclina T/genética , Ciclina T/inmunología , Quinasa 9 Dependiente de la Ciclina/genética , Quinasa 9 Dependiente de la Ciclina/inmunología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/genética , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/patología , Replicación del ADN/efectos de los fármacos , ADN Viral/antagonistas & inhibidores , ADN Viral/inmunología , Genes Inmediatos-Precoces , Genes Reporteros , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/inmunología , Interacciones Huésped-Patógeno , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Modelos Biológicos , Factor B de Elongación Transcripcional Positiva/inmunología , Cultivo Primario de Células , Regiones Promotoras Genéticas , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/virología , Células THP-1 , Talidomida/análogos & derivados , Talidomida/farmacología , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/inmunología , Transcripción Genética , Activación Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacosRESUMEN
An interaction network exists among cells within the brain, maintaining brain homeostasis and ensuring its functional plasticity. In addition to neurons, participating cells include astrocytes, oligodendrocytes, and microglia. Peripheral immune cells, such as monocytes and lymphocytes, have also been found to play an important role in supporting the brain in health and assisting in its repair. Here, we describe the multiple immune-specific modes of cellular dialogue among cells within the mammalian brain and their crosstalk with the periphery in both health and disease. We further suggest that interventions directed at boosting the peripheral immune response can restore the balance between the brain and the immune system and can rewire their communication to modify chronic neurodegenerative diseases.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Inmunoterapia , Enfermedad de Alzheimer/terapia , Animales , Astrocitos/inmunología , Encéfalo/citología , Encéfalo/inmunología , Comunicación Celular/inmunología , Humanos , Microglía/inmunología , Oligodendroglía/inmunologíaRESUMEN
The incidence of age-related dementia is growing with increased longevity, yet there are currently no disease-modifying therapies for these devastating disorders. Studies over the last several years have led to an evolving awareness of the role of the immune system in supporting brain maintenance and repair, displaying a diverse repertoire of functions while orchestrating the crosstalk between the periphery and the brain. Here, we provide insights into the current understanding of therapeutic targets that could be adopted to modulate immune cell fate, either systemically or locally, to defeat brain aging and neurodegeneration.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Humanos , Longevidad , Sistema InmunológicoRESUMEN
Viruses are known for their extremely compact genomes composed almost entirely of protein-coding genes. Nonetheless, four long noncoding RNAs (lncRNAs) are encoded by human cytomegalovirus (HCMV). Although these RNAs accumulate to high levels during lytic infection, their functions remain largely unknown. Here, we show that HCMV-encoded lncRNA4.9 localizes to the viral nuclear replication compartment, and that its depletion restricts viral DNA replication and viral growth. RNA4.9 is transcribed from the HCMV origin of replication (oriLyt) and forms an RNA-DNA hybrid (R-loop) through its G+C-rich 5' end, which may be important for the initiation of viral DNA replication. Furthermore, targeting the RNA4.9 promoter with CRISPR-Cas9 or genetic relocalization of oriLyt leads to reduced levels of the viral single-stranded DNA-binding protein (ssDBP), suggesting that the levels of ssDBP are coupled to the oriLyt activity. We further identified a similar, oriLyt-embedded, G+C-rich lncRNA in murine cytomegalovirus (MCMV). These results indicate that HCMV RNA4.9 plays an important role in regulating viral DNA replication, that the levels of ssDBP are coupled to the oriLyt activity, and that these regulatory features may be conserved among betaherpesviruses.
Asunto(s)
Citomegalovirus/genética , Replicación del ADN , ADN Viral/genética , Proteínas Inmediatas-Precoces/metabolismo , ARN Largo no Codificante/genética , Proteínas Virales/genética , Replicación Viral , Animales , Células Cultivadas , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/microbiología , Infecciones por Citomegalovirus/patología , Regulación Viral de la Expresión Génica , Humanos , Proteínas Inmediatas-Precoces/genética , Ratones , Origen de RéplicaRESUMEN
Monocyte-derived macrophages are essential for recovery after spinal cord injury, but their homing mechanism is poorly understood. Here, we show that although of common origin, the homing of proinflammatory (M1) and the "alternatively activated" anti-inflammatory (M2) macrophages to traumatized spinal cord (SC) was distinctly regulated, neither being through breached blood-brain barrier. The M1 macrophages (Ly6c(hi)CX3CR1(lo)) derived from monocytes homed in a CCL2 chemokine-dependent manner through the adjacent SC leptomeninges. The resolving M2 macrophages (Ly6c(lo)CX3CR1(hi)) derived from monocytes trafficked through a remote blood-cerebrospinal-fluid (CSF) barrier, the brain-ventricular choroid plexus (CP), via VCAM-1-VLA-4 adhesion molecules and epithelial CD73 enzyme for extravasation and epithelial transmigration. Blockage of these determinants, or mechanical CSF flow obstruction, inhibited M2 macrophage recruitment and impaired motor-function recovery. The CP, along with the CSF and the central canal, provided an anti-inflammatory supporting milieu, potentially priming the trafficking monocytes. Overall, our finding demonstrates that the route of monocyte entry to central nervous system provides an instructional environment to shape their function.
Asunto(s)
Plexo Coroideo/inmunología , Macrófagos/inmunología , Traumatismos de la Médula Espinal/inmunología , Médula Espinal/inmunología , 5'-Nucleotidasa/antagonistas & inhibidores , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/inmunología , Adenosina Difosfato/análogos & derivados , Adenosina Difosfato/farmacología , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Receptor 1 de Quimiocinas CX3C , Movimiento Celular/genética , Movimiento Celular/inmunología , Plexo Coroideo/metabolismo , Inhibidores Enzimáticos/farmacología , Citometría de Flujo , Expresión Génica/inmunología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Integrina alfa4beta1/genética , Integrina alfa4beta1/inmunología , Antígenos Comunes de Leucocito/inmunología , Antígenos Comunes de Leucocito/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Meninges/inmunología , Meninges/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Receptores de Quimiocina/genética , Receptores de Quimiocina/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/líquido cefalorraquídeo , Traumatismos de la Médula Espinal/genética , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
The understanding of the dialogue between the brain and the immune system has undergone dramatic changes over the last two decades, with immense impact on the perception of neurodegenerative diseases, mental dysfunction, and many other brain pathologic conditions. Accumulated results have suggested that optimal function of the brain is dependent on support from the immune system, provided that this immune response is tightly controlled. Moreover, in contrast to the previous prevailing dogma, it is now widely accepted that circulating immune cells are needed for coping with brain pathologies and that their optimal effect is dependent on their type, location, and activity. In this perspective, we describe our own scientific journey, reviewing the milestones in attaining this understanding of the brain-immune axis integrated with numerous related studies by others. We then explain their significance in demonstrating the possibility of harnessing the immune system in a well-controlled manner for the treatment of neurodegenerative diseases.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Encéfalo/inmunología , Inmunoterapia/tendencias , Neuroinmunomodulación/fisiología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/terapia , Animales , Encéfalo/fisiopatología , Humanos , Inmunoterapia/métodos , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/fisiopatología , Enfermedades Neurodegenerativas/terapiaRESUMEN
Viral infection during pregnancy is often associated with neuropsychiatric conditions. In mice, exposure of pregnant dams to the viral mimetic poly(I:C), serves as a model that simulates such pathology in the offspring, through a process known as Maternal Immune Activation (MIA). To investigate the mechanism of such effect, we hypothesized that maternal upregulation of Type-I interferon (IFN-I), as part of the dam's antiviral response, might contribute to the damage imposed on the offspring. Using mRNA sequencing and flow cytometry analyses we found that poly(I:C) treatment during pregnancy caused reduced expression of genes related to proliferation and cell cycle in the offspring's microglia relative to controls. This was found to be associated with an IFN-I signature in the embryonic yolk sac, the origin of microglia in development. Neutralizing IFN-I signaling in dams attenuated the effect of MIA on the newborn's microglia, while systemic maternal administration of IFNß was sufficient to mimic the effect of poly(I:C), and led to increased vulnerability of offspring's microglia to subsequent stress. Furthermore, maternal elevation of IFNß resulted in behavioral manifestations reminiscent of neuropsychiatric disorders. In addition, by adopting a "two-hit" experimental paradigm, we show a higher sensitivity of the offspring to postnatal stress subsequent to the maternal IFNß elevation, demonstrated by behavioral irregularities. Our results suggest that maternal upregulation of IFN-I, in response to MIA, interferes with the offspring's programmed microglial developmental cascade, increases their susceptibility to postnatal stress, and leads to behavioral abnormalities.
Asunto(s)
Conducta Animal , Interferón Tipo I/inmunología , Microglía/inmunología , Madres/psicología , Efectos Tardíos de la Exposición Prenatal/inmunología , Estrés Psicológico/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Exposición Materna , Ratones , Ratones Endogámicos C57BL , EmbarazoRESUMEN
The choroid plexus epithelium within the brain ventricles orchestrates blood-derived monocyte entry to the central nervous system under injurious conditions, including when the primary injury site is remote from the brain. Here, we hypothesized that the retinal pigment epithelium (RPE) serves a parallel role, as a gateway for monocyte trafficking to the retina following direct or remote injury. We found elevated expression of genes encoding leukocyte trafficking determinants in mouse RPE as a consequence of retinal glutamate intoxication or optic nerve crush (ONC). Blocking VCAM-1 after ONC interfered with monocyte infiltration into the retina and resulted in a local pro-inflammatory cytokine bias. Live imaging of the injured eye showed monocyte accumulation first in the RPE, and subsequently in the retina, and peripheral leukocytes formed close contact with the RPE Our findings further implied that the ocular milieu can confer monocytes a phenotype advantageous for neuroprotection. These results suggest that the eye utilizes a mechanism of crosstalk with the immune system similar to that of the brain, whereby epithelial barriers serve as gateways for leukocyte entry.
Asunto(s)
Monocitos/inmunología , Epitelio Pigmentado de la Retina/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Receptor 1 de Quimiocinas CX3C , Quimiotaxis de Leucocito , Expresión Génica , Ácido Glutámico/toxicidad , Proteínas Fluorescentes Verdes/genética , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Traumatismos del Nervio Óptico/inmunología , Receptores de Citocinas/genética , Receptores del VIH/genética , Retinitis/inmunología , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
The latent human cytomegalovirus (HCMV) transcriptome has been extremely difficult to define due to the scarcity of naturally latent cells and the complexity of available models. The genomic era offers many approaches to transcriptome profiling that hold great potential for elucidating this challenging issue. The results from two recent studies applying different transcriptomic methodologies and analyses of both experimental and natural samples challenge the dogma of a restricted latency-associated transcription program. Instead, they portray the hallmark of HCMV latent infection as low-level expression of a broad spectrum of canonical viral lytic genes.