RESUMO
Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited antiviral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, â¼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-λ and Tnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.
Assuntos
Enzima de Conversão de Angiotensina 2/imunologia , COVID-19/imunologia , Viroses do Sistema Nervoso Central/imunologia , Microglia/imunologia , SARS-CoV-2/fisiologia , Replicação Viral/imunologia , Enzima de Conversão de Angiotensina 2/genética , Animais , COVID-19/genética , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Viroses do Sistema Nervoso Central/genética , Viroses do Sistema Nervoso Central/virologia , Quimiocinas/genética , Quimiocinas/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Microglia/virologia , Neurônios/imunologia , Neurônios/virologia , Replicação Viral/genéticaRESUMO
The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer's disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host's adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.
Assuntos
Encéfalo/patologia , Viroses do Sistema Nervoso Central/imunologia , Regulação da Expressão Gênica/imunologia , MicroRNAs/metabolismo , Doenças Priônicas/imunologia , Apoptose/genética , Apoptose/imunologia , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/imunologia , Encéfalo/virologia , Viroses do Sistema Nervoso Central/diagnóstico , Viroses do Sistema Nervoso Central/genética , Viroses do Sistema Nervoso Central/virologia , Fator H do Complemento/metabolismo , Citocinas/metabolismo , Humanos , MicroRNAs/análise , MicroRNAs/genética , NF-kappa B/metabolismo , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética , Doenças Priônicas/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismoRESUMO
BACKGROUND: Human immunodeficiency virus (HIV)/AIDS is one of the principal concerns contributing to the global burden and the accompanying deleterious outcomes could not be left unattended. Despite significant advances and innovative research being conducted throughout the globe in order to improve the therapeutic profile of conventionally available antiretroviral (ARV) drugs in the eradication of HIV virus reservoirs, its penetration across the blood-brain barrier (BBB) is still a formidable mission. This makes the central nervous system a dominant and vulnerable site for virus propagation, which ultimately affects the therapeutic potential of the drug administered. Therefore there is an upsurge in the prerequisite of novel technologies to come into play, paving the way for nanotechnology. METHODS: This review primarily provides a comprehensive outline and emphasizes on the nanotechnological techniques employed for the delivery of ARV drugs and their stupendous advantages in overcoming the hurdles associated with the same. RESULTS: The nanotechnological approach bears the potential of site-specific delivery across the BBB via targeting explicit transport processes and provides a sustained release mechanism. Furthermore, different routes of administration explored have also yielded beneficial outcomes for the delivery of ARV drugs. CONCLUSION: The futuristic holistic nanotechnology methods, however, should focus on increasing drug trafficking and permeability across the BBB to ameliorate the therapeutic effect of ARV drugs. Additionally, the domain warrants clinical studies to be undertaken to make the technology commercially viable and a success to deal with the problems of the treatment strategy.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Barreira Hematoencefálica/efeitos dos fármacos , Viroses do Sistema Nervoso Central/tratamento farmacológico , Sistemas de Liberação de Fármacos por Nanopartículas/farmacologia , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Fármacos Anti-HIV/farmacocinética , Barreira Hematoencefálica/metabolismo , Viroses do Sistema Nervoso Central/imunologia , Viroses do Sistema Nervoso Central/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Humanos , Sistemas de Liberação de Fármacos por Nanopartículas/química , Nanomedicina Teranóstica/métodos , Nanomedicina Teranóstica/tendências , Distribuição Tecidual , Resultado do TratamentoRESUMO
Zika virus (ZIKV), a mosquito-borne flavivirus, came into the spotlight in 2016 when it was found to be associated with an increased rate of microcephalic newborns in Brazil. The virus has further been recognized to cause neurologic complications in children and adults in the form of myelitis, encephalitis, acute disseminated encephalomyelitis (ADEM) and Guillain Barre Syndrome in a fraction of infected individuals. With the ultimate goal of identifying correlates of protection to guide the design of an effective vaccine, the study of the immune response to ZIKV infection has become the focus of research worldwide. Both innate and adaptive immune responses seem to be essential for controlling the infection. Induction of sufficient levels of neutralizing antibodies has been strongly correlated with protection against reinfection in various models, while the role of CD8 T cells as antiviral effectors in the CNS has been controversial. In an attempt to improve our understanding regarding the role of ZIKV-induced CD8 T cells in protective immunity inside the CNS, we have expanded on previous studies in intracranially infected mice. In a recent study, we have demonstrated that, peripheral ZIKV infection in adult C57BL/6 mice induces a robust CD8 T cell response that peaks within a week. In the present study, we used B cell deficient as well as wild-type mice to show that there is a race between CXCR3-dependent recruitment of the effector CD8 T cells and local ZIKV replication, and that CD8 T cells are capable of local viral control if they arrive in the brain early after viral invasion, in appropriate numbers and differentiation state. Our data highlight the benefits of considering this subset when designing vaccines against Zika virus.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Viroses do Sistema Nervoso Central/imunologia , Viroses do Sistema Nervoso Central/virologia , Interações Hospedeiro-Patógeno/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/imunologia , Animais , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/virologia , Linfócitos T CD8-Positivos/metabolismo , Viroses do Sistema Nervoso Central/diagnóstico , Viroses do Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Feminino , Imunização , Imunofenotipagem , Contagem de Linfócitos , Depleção Linfocítica , Camundongos , Camundongos Knockout , Carga Viral , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/metabolismoRESUMO
Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, e.g., acute flaccid myelitis (AFM) and multiple sclerosis (MS), where animal models support the pathogenic roles of viruses. In the spinal cord, Theiler's murine encephalomyelitis virus (TMEV) induces an AFM-like disease with gray matter inflammation during the acute phase, 1 week post infection (p.i.), and an MS-like disease with white matter inflammation during the chronic phase, 1 month p.i. Although gut microbiota has been proposed to affect immune responses contributing to pathological conditions in remote organs, including the brain pathophysiology, its precise role in neuroinflammatory diseases is unclear. We infected SJL/J mice with TMEV; harvested feces and spinal cords on days 4 (before onset), 7 (acute phase), and 35 (chronic phase) p.i.; and examined fecal microbiota by 16S rRNA sequencing and CNS transcriptome by RNA sequencing. Although TMEV infection neither decreased microbial diversity nor changed overall microbiome patterns, it increased abundance of individual bacterial genera Marvinbryantia on days 7 and 35 p.i. and Coprococcus on day 35 p.i., whose pattern-matching with CNS transcriptome showed strong correlations: Marvinbryantia with eight T-cell receptor (TCR) genes on day 7 and with seven immunoglobulin (Ig) genes on day 35 p.i.; and Coprococcus with gene expressions of not only TCRs and IgG/IgA, but also major histocompatibility complex (MHC) and complements. The high gene expression of IgA, a component of mucosal immunity, in the CNS was unexpected. However, we observed substantial IgA positive cells and deposition in the CNS, as well as a strong correlation between CNS IgA gene expression and serum anti-TMEV IgA titers. Here, changes in a small number of distinct gut bacteria, but not overall gut microbiota, could affect acute and chronic immune responses, causing AFM- and MS-like lesions in the CNS. Alternatively, activated immune responses would alter the composition of gut microbiota.
Assuntos
Viroses do Sistema Nervoso Central/imunologia , Viroses do Sistema Nervoso Central/microbiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/microbiologia , Microbioma Gastrointestinal , Mielite/imunologia , Mielite/microbiologia , Doenças Neuromusculares/imunologia , Doenças Neuromusculares/microbiologia , Animais , Infecções por Cardiovirus/complicações , Infecções por Cardiovirus/imunologia , Doença Crônica , Biologia Computacional , Imunoglobulina A/imunologia , Camundongos , Theilovirus , Transcriptoma , Regulação para CimaRESUMO
Enterovirus D68 (EV-D68) causes outbreaks of respiratory illness, and there is increasing evidence that it causes outbreaks of acute flaccid myelitis (AFM). There are no licensed therapies to prevent or treat EV-D68 infection or AFM disease. We isolated a panel of EV-D68-reactive human monoclonal antibodies that recognize diverse antigenic variants from participants with prior infection. One potently neutralizing cross-reactive antibody, EV68-228, protected mice from respiratory and neurologic disease when given either before or after infection. Cryo-electron microscopy studies revealed that EV68-228 and another potently neutralizing antibody (EV68-159) bound around the fivefold or threefold axes of symmetry on virion particles, respectively. The structures suggest diverse mechanisms of action by these antibodies. The high potency and effectiveness observed in vivo suggest that antibodies are a mechanistic correlate of protection against AFM disease and are candidates for clinical use in humans with EV-D68 infection.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Viroses do Sistema Nervoso Central/prevenção & controle , Enterovirus Humano D/imunologia , Infecções por Enterovirus/prevenção & controle , Mielite/prevenção & controle , Doenças Neuromusculares/prevenção & controle , Animais , Linfócitos B/imunologia , Linhagem Celular , Viroses do Sistema Nervoso Central/imunologia , Citocinas/imunologia , Infecções por Enterovirus/imunologia , Feminino , Humanos , Pulmão/imunologia , Masculino , Camundongos Knockout , Mielite/imunologia , Doenças Neuromusculares/imunologiaRESUMO
The human neurotropic virus JC Polyomavirus, a member of the Polyomaviridae family, is the opportunistic infectious agent causing progressive multifocal leukoencephalopathy, typically in immunocompromised individuals. The spectrum of underlying reasons for the systemic immunosuppression that permits JCV infection in the central nervous system has evolved over the past 2 decades, and therapeutic immunosuppression arousing JCV infection in the brain has become increasingly prominent as a trigger for PML. Effective immune restoration subsequent to human immunodeficiency virus-related suppression is now recognized as a cause for unexpected deterioration of symptoms in patients with PML, secondary to a rebound inflammatory phenomenon called immune reconstitution inflammatory syndrome, resulting in significantly increased morbidity and mortality in a disease already infamous for its lethality. This review addresses current knowledge regarding JC Polyomavirus, progressive multifocal leukoencephalopathy, progressive multifocal leukoencephalopathy-related immune reconstitution inflammatory syndrome, and the immunocompromised states that incite JC Polyomavirus central nervous system infection, and discusses prospects for the future management of these conditions.
Assuntos
Viroses do Sistema Nervoso Central/imunologia , Síndrome Inflamatória da Reconstituição Imune/etiologia , Hospedeiro Imunocomprometido , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Viroses do Sistema Nervoso Central/complicações , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Síndrome Inflamatória da Reconstituição Imune/virologia , Vírus JC/patogenicidade , Leucoencefalopatia Multifocal Progressiva/fisiopatologia , Leucoencefalopatia Multifocal Progressiva/terapiaRESUMO
Tissue-resident memory (TRM) CD8 T cells provide early frontline defense against regional pathogen reencounter. CD8 TRM are predominantly parked in nonlymphoid tissues and do not circulate. In addition to this anatomic difference, TRM are transcriptionally and phenotypically distinct from central-memory T cells (TCM) and effector-memory T cells (TEM). Moreover, TRM differ phenotypically, functionally, and transcriptionally across barrier tissues (e.g., gastrointestinal tract, respiratory tract, urogenital tract, and skin) and in non-barrier organs (e.g., brain, liver, kidney). In the brain, TRM are governed by a contextual milieu that balances TRM activation and preservation of essential post-mitotic neurons. Factors contributing to the development and maintenance of brain TRM, of which T cell receptor (TCR) signal strength and duration is a central determinant, vary depending on the infectious agent and modulation of TCR signaling by inhibitory markers that quell potentially pathogenic inflammation. This review will explore our current understanding of the context-dependent factors that drive the acquisition of brain (b)TRM phenotype and function, and discuss the contribution of TRM to promoting protective immune responses in situ while maintaining tissue homeostasis.
Assuntos
Encéfalo/imunologia , Linfócitos T CD8-Positivos/imunologia , Viroses do Sistema Nervoso Central/imunologia , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Vírus/imunologia , Animais , Encéfalo/patologia , Encéfalo/virologia , Linfócitos T CD8-Positivos/patologia , Viroses do Sistema Nervoso Central/patologia , Viroses do Sistema Nervoso Central/virologia , Humanos , Memória Imunológica , Inflamação/imunologia , Inflamação/patologia , Inflamação/virologiaRESUMO
An Italian 13-year-old boy immunosuppressed due to kidney transplant presented in November 2018 with acute flaccid paralysis with anterior horn cell involvement resembling the clinical, radiological, and laboratory features of poliomyelitis. Enterovirus was molecularly identified in cerebral spinal fluid and stool samples and the sequence analysis of the VP1 gene of enterovirus genome revealed the presence of Echovirus 30 both in CSF and in stool samples. Echovirus 30 is an emerging neurotropic virus able to cause outbreaks of aseptic meningitis and meningoencephalitis all over the world, but acute flaccid paralysis is not a classical manifestation. A 6-month follow-up revealed a poor outcome with severe motor deficits and only slight improvement in disability. Clinicians must be aware of the possible role of Echovirus 30 in acute flaccid paralysis and active surveillance should consider the possible influence of immunosuppression on the symptoms caused by the widening spectrum of enterovirus infections.
Assuntos
Viroses do Sistema Nervoso Central/imunologia , Viroses do Sistema Nervoso Central/virologia , Infecções por Echovirus/imunologia , Hospedeiro Imunocomprometido , Transplante de Rim , Mielite/imunologia , Mielite/virologia , Doenças Neuromusculares/imunologia , Doenças Neuromusculares/virologia , Adolescente , Enterovirus Humano B , Humanos , Masculino , TransplantadosRESUMO
West Nile Virus (WNV) can result in clinically severe neurologic disease. There is no treatment for WNV infection, but administration of anti-WNV polyclonal human antibody has demonstrated efficacy in animal models. We compared Omr-IgG-am, an immunoglobulin product with high titers of anti-WNV antibody, with intravenous immunoglobulin (IVIG) and normal saline to assess safety and efficacy in patients with WNV neuroinvasive disease as part of a phase I/II, randomized, double-blind, multicenter study in North America. During 2003-2006, a total of 62 hospitalized patients were randomized to receive Omr-IgG-am, standard IVIG, or normal saline (3:1:1). The primary endpoint was medication safety. Secondary endpoints were morbidity and mortality, measured using 4 standardized assessments of cognitive and functional status. The death rate in the study population was 12.9%. No significant differences were found between groups receiving Omr-IgG-am compared with IVIG or saline for either the safety or efficacy endpoints.
Assuntos
Viroses do Sistema Nervoso Central/tratamento farmacológico , Viroses do Sistema Nervoso Central/virologia , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Febre do Nilo Ocidental/tratamento farmacológico , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental , Adulto , Idoso , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/imunologia , Viroses do Sistema Nervoso Central/imunologia , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Febre do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologiaRESUMO
CD8 T cells coordinate immune defenses against viral infections of the central nervous system (CNS). Virus-specific CD8 T cells infiltrate the CNS and differentiate into brain-resident memory CD8 T cells (CD8 bTRM). CD8 bTRM are characterized by a lack of recirculation and expression of phenotypes and transcriptomes distinct from other CD8 T cell memory subsets. CD8 bTRM have been shown to provide durable, autonomous protection against viral reinfection and the resurgence of latent viral infections. CD8 T cells have also been implicated in the development of neural damage following viral infection, which demonstrates that the infiltration of CD8 T cells into the brain can also be pathogenic. In this review, we will explore the residency and maintenance requirements for CD8 bTRM and discuss their roles in controlling viral infections of the brain.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Viroses do Sistema Nervoso Central/imunologia , Memória Imunológica , Animais , Encéfalo/imunologia , Viroses do Sistema Nervoso Central/complicações , HumanosRESUMO
Enteroviruses are potentially linked to the emergence of Acute Flaccid Myelitis (AFM), a rare but very serious condition that affects the nervous system. AFM has been associated with coxsackievirus A16, enterovirus A71 (EVA71) and enterovirus D68 (EVD68). Little is known about host-pathogen interactions for these viruses, and whether immune responses may have a protective or immunopathological role in disease presentations. Towards addressing this issue, we used the Immune Epitope Database to assess the known inventory of B and T cell epitopes from enteroviruses, focusing on data related to human hosts. The extent of conservation in areas that are targets of B and T cell immune responses were examined. This analysis sheds light on regions of the enterovirus polypeptide that can be probed to induce a specific or cross-reactive B or T cell the immune response to enteroviruses, with a particular focus on coxsackievirus A16, EVA71 and EVD68. In addition, these analyses reveal the current gap-of-knowledge in the T and B cell immune responses that future studies should aim to address.
Assuntos
Antígenos Virais/genética , Linfócitos B/imunologia , Viroses do Sistema Nervoso Central/imunologia , Infecções por Coxsackievirus/imunologia , Enterovirus Humano A/fisiologia , Enterovirus Humano D/fisiologia , Epitopos Imunodominantes/genética , Mielite/imunologia , Doenças Neuromusculares/imunologia , Linfócitos T/imunologia , Antígenos Virais/imunologia , Biologia Computacional , Reações Cruzadas , Mapeamento de Epitopos , Interações Hospedeiro-Patógeno , Humanos , Imunidade Celular , Epitopos Imunodominantes/imunologia , Receptores de Antígenos/metabolismo , Análise de Sequência de RNA , Especificidade da EspécieRESUMO
A variety of viruses can induce central nervous system (CNS) infections and neurological diseases, although the incidence is rare. Similar to peripheral infections, IFNα/ß induction and signaling constitutes a first line of defense to limit virus dissemination. However, CNS-resident cells differ widely in their repertoire and magnitude of both basal and inducible components in the IFNα/ß pathway. While microglia as resident myeloid cells have been implicated as prominent sentinels of CNS invading pathogens or insults, astrocytes are emerging as key responders to many neurotropic RNA virus infections. Focusing on RNA viruses, this review discusses the role of astrocytes as IFNα/ß inducers and responders and touches on the role of IFNα/ß receptor signaling in regulating myeloid cell activation and IFNγ responsiveness. A summary picture emerges implicating IFNα/ß not only as key in establishing the classical "antiviral" state, but also orchestrating cell mobility and IFNγ-mediated effector functions.
Assuntos
Viroses do Sistema Nervoso Central/imunologia , Interferon-alfa/imunologia , Interferon beta/imunologia , Transdução de Sinais , Animais , Astrócitos/virologia , Humanos , Interferon gama/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/virologia , Vírus de RNARESUMO
Viral infections of the central nervous system are accompanied by the expression of cytokines and chemokines that can be critical for the control of viral replication in the brain. The outcomes of cytokine/chemokine signaling in neural cells vary widely, with cell-specific effects on cellular activity, proliferation, and survival. Neural stem/progenitor cells (NSPCs) are often altered during viral infections, through direct infection by the virus or by the influence of immune cell activity or cytokine/chemokine signaling. However, it has been challenging to dissect the contribution of the virus and specific inflammatory mediators during an infection. In addition to initiating an antiviral program in infected NSPCs, cytokines/chemokines can induce multiple changes in NSPC behavior that can perturb NSPC numbers, differentiation into other neural cells, and migration to sites of injury, and ultimately brain development and repair. The focus of this review was to dissect the effects of common antiviral cytokines and chemokines on NSPC activity, and to consider the subsequent pathological consequences for the host from changes in NSPC function.
Assuntos
Viroses do Sistema Nervoso Central/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Células-Tronco Neurais/imunologia , Transdução de Sinais , Animais , Encéfalo/imunologia , Células Cultivadas , Humanos , Inflamação , Camundongos , Replicação Viral/imunologiaRESUMO
Infection with Human Immunodeficiency Virus (HIV)-1 continues to cause HIV-associated neurocognitive disorders despite combined antiretroviral therapy. Interferons (IFNs) are important for any antiviral immune response, but the lasting production of IFNα causes exhaustive activation leading eventually to progression to AIDS. Expression of IFNα in the HIV-exposed central nervous system has been linked to cognitive impairment and inflammatory neuropathology. In contrast, IFNß exerts anti-inflammatory effects, appears to control, at least temporarily, lentiviral infection in the brain and provides neuroprotection. The dichotomy of type I IFN effects on HIV-1 infection and the associated brain injury will be discussed in this review, because the underlying mechanisms require further investigation to allow harnessing these innate immune factors for therapeutic purposes.
Assuntos
Complexo AIDS Demência/imunologia , Viroses do Sistema Nervoso Central/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Interferon Tipo I/imunologia , Animais , Antivirais/uso terapêutico , Encéfalo/patologia , Encéfalo/virologia , Humanos , Interferon Tipo I/uso terapêutico , Interferon-alfa/imunologia , Interferon-alfa/uso terapêutico , Interferon beta/imunologia , Interferon beta/uso terapêutico , Camundongos , Replicação Viral/efeitos dos fármacosRESUMO
Viral infection in the brain can be acute or chronic, with the responses often producing foci of increasingly cytotoxic inflammation. This can lead to effects beyond the central nervous system (CNS). To stimulate discussion, this commentary addresses four questions: What drives the development of human immunodeficiency virus (HIV)-associated neurocognitive disorders, does the phenotype of macrophages in the CNS spur development of HIV encephalitis (HIVE), does continual activation of astrocytes drive the development of HIV-associated neurocognitive disorders/subclinical disease, and neuroinflammation: friend or foe? A unifying theory that connects each question is the issue of continued activation of glial cells, even in the apparent absence of simian immunodeficiency virus/HIV in the CNS. As the CNS innate immune system is distinct from the rest of the body, it is likely there could be a number of activation profiles not observed elsewhere.
Assuntos
Viroses do Sistema Nervoso Central/imunologia , Infecções por HIV/imunologia , Inflamação/virologia , Transtornos Neurocognitivos/imunologia , Animais , Astrócitos/imunologia , Astrócitos/virologia , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/virologia , Viroses do Sistema Nervoso Central/patologia , Doença Crônica , HIV , Infecções por HIV/complicações , Infecções por HIV/patologia , Humanos , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/virologia , Transtornos Neurocognitivos/virologia , Neuroglia/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/patogenicidadeRESUMO
Chemokines (chemotactic cytokines) are involved in a wide variety of biological processes. Following microbial infection, there is often robust chemokine signaling elicited from infected cells, which contributes to both innate and adaptive immune responses that control growth of the invading pathogen. Infection of the central nervous system (CNS) by the neuroadapted John Howard Mueller (JHM) strain of mouse hepatitis virus (JHMV) provides an excellent example of how chemokines aid in host defense as well as contribute to disease. Intracranial inoculation of the CNS of susceptible mice with JHMV results in an acute encephalomyelitis characterized by widespread dissemination of virus throughout the parenchyma. Virus-specific T cells are recruited to the CNS, and control viral replication through release of antiviral cytokines and cytolytic activity. Sterile immunity is not acquired, and virus will persist primarily in white matter tracts leading to chronic neuroinflammation and demyelination. Chemokines are expressed and contribute to defense as well as chronic disease by attracting targeted populations of leukocytes to the CNS. The T cell chemoattractant chemokine CXCL10 (interferon-inducible protein 10 kDa, IP-10) is prominently expressed in both stages of disease, and serves to attract activated T and B lymphocytes expressing CXC chemokine receptor 3 (CXCR3), the receptor for CXCL10. Functional studies that have blocked expression of either CXCL10 or CXCR3 illuminate the important role of this signaling pathway in host defense and neurodegeneration in a model of viral-induced neurologic disease.
Assuntos
Viroses do Sistema Nervoso Central/imunologia , Quimiocina CXCL10/imunologia , Infecções por Coronavirus/imunologia , Doenças Desmielinizantes/imunologia , Vírus da Hepatite Murina/imunologia , Animais , Viroses do Sistema Nervoso Central/patologia , Quimiocina CXCL10/genética , Fatores Quimiotáticos , Infecções por Coronavirus/patologia , Doenças Desmielinizantes/virologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Vírus da Hepatite Murina/patogenicidade , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Transdução de Sinais , Linfócitos T/imunologiaRESUMO
INTRODUCTION: Previous work from our laboratory has demonstrated in vivo persistence of CD103+ CD69+ brain resident memory CD8+ T-cells (bTRM ) following viral infection, and that the PD-1: PD-L1 pathway promotes development of these TRM cells within the brain. Although glial cells express low basal levels of PD-L1, its expression is upregulated upon IFN-γ-treatment, and they have been shown to modulate antiviral T-cell effector responses through the PD-1: PD-L1 pathway. METHODS: We performed flow cytometric analysis of cells from co-cultures of mixed glia and CD8+ T-cells obtained from wild type mice to investigate the role of glial cells in the development of bTRM . RESULTS: In this study, we show that interactions between reactive glia and anti-CD3 Ab-stimulated CD8+ T-cells promote development of CD103+ CD69+ CD8+ T-cells through engagement of the PD-1: PD-L1 pathway. These studies used co-cultures of primary murine glial cells obtained from WT animals along with CD8+ T-cells obtained from either WT or PD-1 KO mice. We found that αCD3 Ab-stimulated CD8+ T-cells from WT animals increased expression of CD103 and CD69 when co-cultured with primary murine glial cells. In contrast, significantly reduced expression of CD103 and CD69 was observed using CD8+ T-cells from PD-1 KO mice. We also observed that reactive glia promoted high levels of CD127, a marker of memory precursor effector cells (MPEC), on CD69+ CD8+ T-cells, which promotes development of TRM cells. Interestingly, results obtained using T-cells from PD-1 KO animals showed significantly reduced expression of CD127 on CD69+ CD8+ cells. Additionally, blocking of glial PD-L1 resulted in decreased expression of CD103, along with reduced CD127 on CD69+ CD8+ T-cells. CONCLUSIONS: Taken together, these results demonstrate a role for activated glia in promoting development of bTRM through the PD-1: PD-L1 pathway.
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Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Neuroglia/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígeno B7-H1/imunologia , Encéfalo/citologia , Encéfalo/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Viroses do Sistema Nervoso Central/imunologia , Viroses do Sistema Nervoso Central/virologia , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Humanos , Cadeias alfa de Integrinas/metabolismo , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muromegalovirus/imunologia , Neuroglia/metabolismo , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologiaRESUMO
PURPOSE OF REVIEW: Although viral infections of the central nervous system (CNS) are known to acutely cause pathology in the form of cytokine-mediated neural tissue damage and inflammation, the pathophysiology of neurologic sequelae after viral clearance is incompletely understood. RECENT FINDINGS: Alterations in microglial and glial biology in response to initial infiltration of immune cells that persist within the CNS have recently been shown to promote neuronal dysfunction and cognitive deficits in animal models of viral encephalitis. SUMMARY: The current review summarizes the current knowledge on the possible role of innate immune signaling during acute infections as triggers of neurologic sequelae that persist, and may even worsen, after clearance of viral infections within the CNS.
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Viroses do Sistema Nervoso Central/imunologia , Neurônios/virologia , Animais , Viroses do Sistema Nervoso Central/patologia , Citocinas , Humanos , Inflamação/patologia , Inflamação/virologiaRESUMO
The central nervous system (CNS) is an immunologically specialized organ where restrictive barrier structures protect the parenchyma from inflammation and infection. This protection is important in preventing damage to non-renewable resident cell populations, such as neurons, responsible for functions ranging from executive to autonomic. Despite these barriers, the CNS can be infected through several entry portals, giving rise to meningitis and encephalitis. Following infection, resident cells recruit peripherally derived immune cells to sites of viral infection. In this review, we discuss recent advances in immune recruitment and entry at barrier structures as well as current immunotherapeutic strategies for the treatment of persistent viral infections.