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1.
J Environ Pathol Toxicol Oncol ; 40(3): 37-49, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34587403

RESUMO

It has now been almost a year since the emergence of the deadly SARS-CoV-2 with millions of people losing their lives due to resultant COVID-19. Apart from the well-known consequences of respiratory illnesses, it has even effortlessly mapped itself into the nervous system through routes like blood, CSF, neurons, and olfactory cells. Interestingly, the interaction of SARS-CoV-2 with the nervous system cells like neurons, microglia, and astrocytes has been a factor to worsen COVID-19 through its neuroinflammatory actions. The release of cytokines due to astrocyte and microglial activation could progress towards the most anticipated cytokine storm proving to be detrimental in the management of COVID-19. Such hyper-inflammatory conditions could make the BBB vulnerable, encouraging excessive viral particles into the CNS, leading to further neurodegenerative pathologies like Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and Multiple Sclerosis. Excessive neuroinflammation and neurodegeneration being the anticipated root causes of these multiple conditions, it is also essential to look into other factors that synergistically enhance the worsening of these diseases in COVID-19 patients for which additional studies are essential.


Assuntos
COVID-19/etiologia , Inflamação/virologia , Doenças Neurodegenerativas/patologia , SARS-CoV-2/patogenicidade , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Inflamação/patologia , Microglia/patologia , Microglia/virologia , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Doenças Neurodegenerativas/virologia , Neurônios/patologia , Neurônios/virologia
2.
Front Immunol ; 12: 730088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484241

RESUMO

In December 2019, a new viral disease emerged and quickly spread all around the world. In March 2020, the COVID-19 outbreak was classified as a global pandemic and by June 2021, the number of infected people grew to over 170 million. Along with the patients' mild-to-severe respiratory symptoms, reports on probable central nervous system (CNS) effects appeared shortly, raising concerns about the possible long-term detrimental effects on human cognition. It remains unresolved whether the neurological symptoms are caused directly by the SARS-CoV-2 infiltration in the brain, indirectly by secondary immune effects of a cytokine storm and antibody overproduction, or as a consequence of systemic hypoxia-mediated microglia activation. In severe COVID-19 cases with impaired lung capacity, hypoxia is an anticipated subsidiary event that can cause progressive and irreversible damage to neurons. To resolve this problem, intensive research is currently ongoing, which seeks to evaluate the SARS-CoV-2 virus' neuroinvasive potential and the examination of the antibody and autoantibody generation upon infection, as well as the effects of prolonged systemic hypoxia on the CNS. In this review, we summarize the current research on the possible interplay of the SARS-CoV-2 effects on the lung, especially on alveolar macrophages and direct and indirect effects on the brain, with special emphasis on microglia, as a possible culprit of neurological manifestation during COVID-19.


Assuntos
COVID-19/complicações , Infecções do Sistema Nervoso Central/complicações , Infecções do Sistema Nervoso Central/virologia , Pulmão/virologia , SARS-CoV-2/patogenicidade , COVID-19/imunologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Humanos , Pulmão/imunologia , Microglia/imunologia , Microglia/patologia , Microglia/virologia , Doenças do Sistema Nervoso/virologia , SARS-CoV-2/imunologia
3.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360004

RESUMO

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging.


Assuntos
Envelhecimento , Encéfalo/fisiopatologia , Inflamação/fisiopatologia , Microglia/virologia , Viroses/fisiopatologia , Animais , Encéfalo/imunologia , Encéfalo/virologia , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/virologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Microglia/imunologia , Microglia/patologia , SARS-CoV-2/fisiologia , Viroses/imunologia , Viroses/virologia
4.
Front Immunol ; 12: 672415, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093573

RESUMO

Humanized bone marrow-liver-thymic (hu-BLT) mice develop a functional immune system in periphery, nevertheless, have a limited reconstitution of human myeloid cells, especially microglia, in CNS. Further, whether bone marrow derived hematopoietic stem and progenitor cells (HSPCs) can enter the brain and differentiate into microglia in adults remains controversial. To close these gaps, in this study we unambiguously demonstrated that human microglia in CNS were extensively reconstituted in adult NOG mice with human interleukin-34 transgene (hIL34 Tg) from circulating CD34+ HSPCs, nonetheless not in hu-BLT NOG mice, providing strong evidence that human CD34+ HSPCs can enter adult brain and differentiate into microglia in CNS in the presence of hIL34. Further, the human microglia in the CNS of hu-BLT-hIL34 NOG mice robustly supported HIV-1 infection reenforcing the notion that microglia are the most important target cells of HIV-1 in CNS and demonstrating its great potential as an in vivo model for studying HIV-1 pathogenesis and evaluating curative therapeutics in both periphery and CNS compartments.


Assuntos
Modelos Animais de Doenças , Infecções por HIV/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Interleucinas , Microglia/virologia , Animais , Encéfalo/virologia , Diferenciação Celular , HIV-1 , Humanos , Interleucinas/genética , Camundongos , Camundongos Transgênicos , Microglia/citologia , Transgenes
5.
J Biol Chem ; 297(1): 100845, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34052228

RESUMO

Alzheimer's disease (AD) is a devastating fatal neurodegenerative disease. An alternative to the amyloid cascade hypothesis is that a viral infection is key to the etiology of late-onset AD, with ß-amyloid (Aß) peptides playing a protective role. In the current study, young 5XFAD mice that overexpress mutant human amyloid precursor protein with the Swedish, Florida, and London familial AD mutations were infected with one of two strains of herpes simplex virus 1 (HSV-1), 17syn+ and McKrae, at three different doses. Contrary to previous work, 5XFAD genotype failed to protect mice against HSV-1 infection. The region- and cell-specific tropisms of HSV-1 were not affected by the 5XFAD genotype, indicating that host-pathogen interactions were not altered. Seven- to ten-month-old 5XFAD animals in which extracellular Aß aggregates were abundant showed slightly better survival rate relative to their wild-type (WT) littermates, although the difference was not statistically significant. In these 5XFAD mice, HSV-1 replication centers were partially excluded from the brain areas with high densities of Aß aggregates. Aß aggregates were free of HSV-1 viral particles, and the limited viral invasion to areas with a high density of Aß aggregates was attributed to phagocytic activity of reactive microglia. In the oldest mice (12-15 months old), the survival rate did not differ between 5XFAD and WT littermates. While the current study questions the antiviral role of Aß, it neither supports nor refutes the viral etiology hypothesis of late-onset AD.


Assuntos
Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Interações Hospedeiro-Patógeno/genética , Viroses/genética , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/virologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/patologia , Encéfalo/virologia , Modelos Animais de Doenças , Herpes Simples/genética , Herpes Simples/patologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Humanos , Camundongos , Camundongos Transgênicos , Microglia/patologia , Microglia/virologia , Presenilina-1/genética , Viroses/complicações , Viroses/patologia , Viroses/virologia , Replicação Viral/genética
6.
Signal Transduct Target Ther ; 6(1): 169, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895780

RESUMO

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.


Assuntos
Encefalopatias/metabolismo , Encéfalo/metabolismo , COVID-19/metabolismo , Bulbo Olfatório/metabolismo , SARS-CoV-2/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/virologia , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/patologia , Encefalopatias/virologia , COVID-19/patologia , Modelos Animais de Doenças , Humanos , Macaca mulatta , Microglia/metabolismo , Microglia/patologia , Microglia/virologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/virologia , Bulbo Olfatório/patologia , Bulbo Olfatório/virologia
7.
J Exp Med ; 218(5)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33630019

RESUMO

Congenital human cytomegalovirus (cHCMV) infection of the brain is associated with a wide range of neurocognitive sequelae. Using infection of newborn mice with mouse cytomegalovirus (MCMV) as a reliable model that recapitulates many aspects of cHCMV infection, including disseminated infection, CNS infection, altered neurodevelopment, and sensorineural hearing loss, we have previously shown that mitigation of inflammation prevented alterations in cerebellar development, suggesting that host inflammatory factors are key drivers of neurodevelopmental defects. Here, we show that MCMV infection causes a dramatic increase in the expression of the microglia-derived chemokines CXCL9/CXCL10, which recruit NK and ILC1 cells into the brain in a CXCR3-dependent manner. Surprisingly, brain-infiltrating innate immune cells not only were unable to control virus infection in the brain but also orchestrated pathological inflammatory responses, which lead to delays in cerebellar morphogenesis. Our results identify NK and ILC1 cells as the major mediators of immunopathology in response to virus infection in the developing CNS, which can be prevented by anti-IFN-γ antibodies.


Assuntos
Encéfalo/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Encéfalo/virologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Quimiocina CXCL9/metabolismo , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/virologia , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Inata/imunologia , Inflamação/genética , Inflamação/virologia , Células Matadoras Naturais/metabolismo , Linfócitos/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Microglia/virologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo
8.
Ann Med ; 53(1): 43-69, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-32841065

RESUMO

The development of effective combined anti-retroviral therapy (cART) led to a significant reduction in the death rate associated with human immunodeficiency virus type 1 (HIV-1) infection. However, recent studies indicate that considerably more than 50% of all HIV-1 infected patients develop HIV-1-associated neurocognitive disorder (HAND). Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS), and so, are also likely to contribute to the neurotoxicity observed in HAND. The activation of microglia induces the release of pro-inflammatory markers and altered secretion of cytokines, chemokines, secondary messengers, and reactive oxygen species (ROS) which activate signalling pathways that initiate neuroinflammation. In turn, ROS and inflammation also play critical roles in HAND. However, more efforts are required to understand the physiology of microglia and the processes involved in their activation in order to better understand the how HIV-1-infected microglia are involved in the development of HAND. In this review, we summarize the current state of knowledge about the involvement of oxidative stress mechanisms and role of HIV-induced ROS in the development of HAND. We also examine the academic literature regarding crucial HIV-1 pathogenicity factors implicated in neurotoxicity and inflammation in order to identify molecular pathways that could serve as potential therapeutic targets for treatment of this disease. KEY MESSAGES Neuroinflammation and excitotoxicity mechanisms are crucial in the pathogenesis of HAND. CNS infiltration by HIV-1 and immune cells through the blood brain barrier is a key process involved in the pathogenicity of HAND. Factors including calcium dysregulation and autophagy are the main challenges involved in HAND.


Assuntos
Sistema Nervoso Central/virologia , Infecções por HIV/psicologia , HIV-1 , Microglia/virologia , Transtornos Neurocognitivos/virologia , Animais , Infecções por HIV/virologia , Humanos , Inflamação Neurogênica , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais
9.
Retrovirology ; 17(1): 35, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213476

RESUMO

BACKGROUND: HIV associated neurocognitive disorders cause significant morbidity and mortality despite the advent of highly active antiretroviral therapy. A deeper understanding of fundamental mechanisms underlying HIV infection and pathogenesis in the central nervous system is warranted. Microglia are resident myeloid cells of the brain that are readily infected by HIV and may constitute a CNS reservoir. We evaluated two microglial model cell lines (C20, HMC3) and two sources of primary cell-derived microglia (monocyte-derived microglia [MMG] and induced pluripotent stem cell-derived microglia [iPSC-MG]) as potential model systems for studying HIV-microglia interactions. RESULTS: All four microglial model cells expressed typical myeloid markers with the exception of low or absent CD45 and CD11b expression by C20 and HMC3, and all four expressed the microglia-specific markers P2RY12 and TMEM119. Marked differences were observed upon gene expression profiling, however, indicating that MMG and iPSC-MG cluster closely together with primary human microglial cells, while C20 and HMC3 were similar to each other but very different from primary microglia. Expression of HIV-relevant genes also revealed important differences, with iPSC-MG and MMG expressing relevant genes at levels more closely resembling primary microglia. iPSC-MG and MMG were readily infected with R5-tropic HIV, while C20 and HMC3 lack CD4 and require pseudotyping for infection. Despite many similarities, HIV replication dynamics and HIV-1 particle capture by Siglec-1 differed markedly between the MMG and iPSC-MG. CONCLUSIONS: MMG and iPSC-MG appear to be viable microglial models that are susceptible to HIV infection and bear more similarities to authentic microglia than two transformed microglia cell lines. The observed differences in HIV replication and particle capture between MMG and iPSC-MG warrant further study.


Assuntos
HIV-1/fisiologia , HIV-1/patogenicidade , Microglia/virologia , Modelos Biológicos , Complexo AIDS Demência/virologia , Biomarcadores/metabolismo , Diferenciação Celular , Linhagem Celular Transformada , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Microglia/citologia , Microglia/metabolismo , Monócitos/citologia , Vírion/metabolismo , Replicação Viral/genética
10.
Viruses ; 12(11)2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198269

RESUMO

Both substance use disorder and HIV infection continue to affect many individuals. Both have untoward effects on the brain, and the two conditions often co-exist. In the brain, macrophages and microglia are infectable by HIV, and these cells are also targets for the effects of drugs of abuse, such as the psychostimulant methamphetamine. To determine the interaction of HIV and methamphetamine, we isolated microglia and brain macrophages from SIV-infected rhesus monkeys that were treated with or without methamphetamine. Cells were subjected to single-cell RNA sequencing and results were analyzed by statistical and bioinformatic analysis. In the animals treated with methamphetamine, a significantly increased proportion of the microglia and/or macrophages were infected by SIV. In addition, gene encoding functions in cell death pathways were increased, and the brain-derived neurotropic factor pathway was inhibited. The gene expression patterns in infected cells did not cluster separately from uninfected cells, but clusters comprised of microglia and/or macrophages from methamphetamine-treated animals differed in neuroinflammatory and metabolic pathways from those comprised of cells from untreated animals. Methamphetamine increases CNS infection by SIV and has adverse effects on both infected and uninfected microglia and brain macrophages, highlighting the dual and interacting harms of HIV infection and drug abuse on the brain.


Assuntos
Macrófagos/metabolismo , Macrófagos/virologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metanfetamina/farmacologia , Microglia/metabolismo , Microglia/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Animais , Biomarcadores , Morte Celular , Biologia Computacional , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Mediadores da Inflamação , Macaca mulatta , Macrófagos/imunologia , Microglia/imunologia , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/psicologia , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Análise de Célula Única , Carga Viral
11.
Front Immunol ; 11: 565521, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013930

RESUMO

Neurological disorders caused by neuroviral infections are an obvious pathogenic manifestation. However, non-neurotropic viruses or peripheral viral infections pose a considerable challenge as their neuropathological manifestations do not emerge because of primary infection. Their secondary or bystander pathologies develop much later, like a syndrome, during and after the recovery of patients from the primary disease. Massive inflammation caused by peripheral viral infections can trigger multiple neurological anomalies. These neurological damages may range from a general cognitive and motor dysfunction up to a wide spectrum of CNS anomalies, such as Acute Necrotizing Hemorrhagic Encephalopathy, Guillain-Barré syndrome, Encephalitis, Meningitis, anxiety, and other audio-visual disabilities. Peripheral viruses like Measles virus, Enteroviruses, Influenza viruses (HIN1 series), SARS-CoV-1, MERS-CoV, and, recently, SARS-CoV-2 are reported to cause various neurological manifestations in patients and are proven to be neuropathogenic even in cellular and animal model systems. This review presents a comprehensive picture of CNS susceptibilities toward these peripheral viral infections and explains some common underlying themes of their neuropathology in the human brain.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Inflamação Neurogênica/complicações , Inflamação Neurogênica/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Vírus da SARS/imunologia , Síndrome Respiratória Aguda Grave/complicações , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/virologia , COVID-19 , Infecções por Coronavirus/virologia , Citocinas/sangue , Modelos Animais de Doenças , Humanos , Microglia/imunologia , Microglia/virologia , Inflamação Neurogênica/virologia , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia
12.
ASN Neuro ; 12: 1759091420954960, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32878468

RESUMO

With confirmed coronavirus disease 2019 (COVID-19) cases surpassing the 18 million mark around the globe, there is an imperative need to gain comprehensive understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the main clinical manifestations of COVID-19 are associated with respiratory or intestinal symptoms, reports of neurological signs and symptoms are increasing. The etiology of these neurological manifestations remains obscure, and probably involves several direct pathways, not excluding the direct entry of the virus to the central nervous system (CNS) through the olfactory epithelium, circumventricular organs, or disrupted blood-brain barrier. Furthermore, neuroinflammation might occur in response to the strong systemic cytokine storm described for COVID-19, or due to dysregulation of the CNS rennin-angiotensin system. Descriptions of neurological manifestations in patients in the previous coronavirus (CoV) outbreaks have been numerous for the SARS-CoV and lesser for Middle East respiratory syndrome coronavirus (MERS-CoV). Strong evidence from patients and experimental models suggests that some human variants of CoV have the ability to reach the CNS and that neurons, astrocytes, and/or microglia can be target cells for CoV. A growing body of evidence shows that astrocytes and microglia have a major role in neuroinflammation, responding to local CNS inflammation and/or to disbalanced peripheral inflammation. This is another potential mechanism for SARS-CoV-2 damage to the CNS. In this comprehensive review, we will summarize the known neurological manifestations of SARS-CoV-2, SARS-CoV and MERS-CoV; explore the potential role for astrocytes and microglia in the infection and neuroinflammation; and compare them with the previously described human and animal CoV that showed neurotropism to propose possible underlying mechanisms.


Assuntos
Astrócitos/virologia , Betacoronavirus , Sistema Nervoso Central/virologia , Infecções por Coronavirus , Microglia/virologia , Pandemias , Pneumonia Viral , Animais , COVID-19 , Humanos , Inflamação/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio , Vírus da SARS , SARS-CoV-2
13.
J Virol ; 94(23)2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-32938766

RESUMO

The role of a signaling pathway through macrophage colony-stimulating factor (MCSF) and its receptor, macrophage colony-stimulating factor 1 receptor (CSF1R), during experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE) was studied by two different approaches. First, we evaluated the effect of stimulation of the MCSF/CSF1R axis before infection. Exogenous MCSF (40 µg/kg of body weight intraperitoneally [i.p.]) was administered once daily to BALB/c mice on days 4 and 2 before intranasal infection with 2,500 PFU of HSV-1. MCSF treatment significantly increased mouse survival compared to saline (50% versus 10%; P = 0.0169). On day 6 postinfection (p.i.), brain viral titers were significantly decreased, whereas beta interferon (IFN-ß) was significantly increased in mice treated with MCSF compared to mice treated with saline. The number of CD68+ (a phagocytosis marker) microglial cells was significantly increased in MCSF-treated mice compared to the saline-treated group. Secondly, we conditionally depleted CSF1R on microglial cells of CSF1R-loxP-CX3CR1-cre/ERT2 mice (in a C57BL/6 background) through induction with tamoxifen. The mice were then infected intranasally with 600,000 PFU of HSV-1. The survival rate of mice depleted of CSF1R (knockout [KO] mice) was significantly lower than that of wild-type (WT) mice (0% versus 67%). Brain viral titers and cytokine/chemokine levels were significantly higher in KO than in WT animals on day 6 p.i. Furthermore, increased infiltration of monocytes into the brains of WT mice was seen on day 6 p.i., but not in KO mice. Our results suggest that microglial cells are essential to control HSE at early stages of the disease and that the MCSF/CSF1R axis could be a therapeutic target to regulate their response to infection.IMPORTANCE Microglia appear to be one of the principal regulators of neuroinflammation in the central nervous system (CNS). An increasing number of studies have demonstrated that the activation of microglia could result in either beneficial or detrimental effects in different CNS disorders. Hence, the role of microglia during herpes simplex virus encephalitis (HSE) has not been fully characterized. Using experimental mouse models, we showed that an early activation of the MCSF/CSF1R axis improved the outcome of the disease, possibly by inducing a proliferation of microglia. In contrast, depletion of microglia before HSV-1 infection worsened the prognosis of HSE. Thus, an early microglial response followed by sustained infiltration of monocytes and T cells into the brain seem to be key components for a better clinical outcome. These data suggest that microglia could be a potential target for immunomodulatory strategies combined with antiviral therapy to better control the outcome of this devastating disease.


Assuntos
Encefalite por Herpes Simples/metabolismo , Herpesvirus Humano 1/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Microglia/metabolismo , Microglia/virologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Animais , Encéfalo/virologia , Sistema Nervoso Central/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Fator Estimulador de Colônias de Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Fagocitose , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Carga Viral
14.
J Virol ; 94(20)2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32796063

RESUMO

Alpha/beta interferon (IFN-α/ß) signaling through the IFN-α/ß receptor (IFNAR) is essential to limit virus dissemination throughout the central nervous system (CNS) following many neurotropic virus infections. However, the distinct expression patterns of factors associated with the IFN-α/ß pathway in different CNS resident cell populations implicate complex cooperative pathways in IFN-α/ß induction and responsiveness. Here we show that mice devoid of IFNAR1 signaling in calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) expressing neurons (CaMKIIcre:IFNARfl/fl mice) infected with a mildly pathogenic neurotropic coronavirus (mouse hepatitis virus A59 strain [MHV-A59]) developed severe encephalomyelitis with hind-limb paralysis and succumbed within 7 days. Increased virus spread in CaMKIIcre:IFNARfl/fl mice compared to IFNARfl/fl mice affected neurons not only in the forebrain but also in the mid-hind brain and spinal cords but excluded the cerebellum. Infection was also increased in glia. The lack of viral control in CaMKIIcre:IFNARfl/fl relative to control mice coincided with sustained Cxcl1 and Ccl2 mRNAs but a decrease in mRNA levels of IFNα/ß pathway genes as well as Il6, Tnf, and Il1ß between days 4 and 6 postinfection (p.i.). T cell accumulation and IFN-γ production, an essential component of virus control, were not altered. However, IFN-γ responsiveness was impaired in microglia/macrophages irrespective of similar pSTAT1 nuclear translocation as in infected controls. The results reveal how perturbation of IFN-α/ß signaling in neurons can worsen disease course and disrupt complex interactions between the IFN-α/ß and IFN-γ pathways in achieving optimal antiviral responses.IMPORTANCE IFN-α/ß induction limits CNS viral spread by establishing an antiviral state, but also promotes blood brain barrier integrity, adaptive immunity, and activation of microglia/macrophages. However, the extent to which glial or neuronal signaling contributes to these diverse IFN-α/ß functions is poorly understood. Using a neurotropic mouse hepatitis virus encephalomyelitis model, this study demonstrated an essential role of IFN-α/ß receptor 1 (IFNAR1) specifically in neurons to control virus spread, regulate IFN-γ signaling, and prevent acute mortality. The results support the notion that effective neuronal IFNAR1 signaling compensates for their low basal expression of genes in the IFN-α/ß pathway compared to glia. The data further highlight the importance of tightly regulated communication between the IFN-α/ß and IFN-γ signaling pathways to optimize antiviral IFN-γ activity.


Assuntos
Sistema Nervoso Central/virologia , Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Sistema Nervoso Central/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Encefalomielite/imunologia , Encefalomielite/virologia , Macrófagos/virologia , Camundongos , Camundongos Mutantes , Microglia/virologia , Vírus da Hepatite Murina/fisiologia , Neurônios/virologia , Infiltração de Neutrófilos , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Replicação Viral
15.
PLoS Negl Trop Dis ; 14(7): e0008413, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628667

RESUMO

Global Zika virus (ZIKV) outbreaks and their link to microcephaly have raised major public health concerns. However, the mechanism of maternal-fetal transmission remains largely unknown. In this study, we determined the role of yolk sac (YS) microglial progenitors in a mouse model of ZIKV vertical transmission. We found that embryonic (E) days 6.5-E8.5 were a critical window for ZIKV infection that resulted in fetal demise and microcephaly, and YS microglial progenitors were susceptible to ZIKV infection. Ablation of YS microglial progenitors significantly reduced the viral load in both the YS and the embryonic brain. Taken together, these results support the hypothesis that YS microglial progenitors serve as "Trojan horses," contributing to ZIKV fetal brain dissemination and congenital brain defects.


Assuntos
Feto/patologia , Microcefalia/patologia , Microglia/virologia , Complicações Infecciosas na Gravidez/patologia , Infecção por Zika virus/patologia , Zika virus/isolamento & purificação , Animais , Encéfalo/virologia , Modelos Animais de Doenças , Feminino , Feto/virologia , Humanos , Transmissão Vertical de Doenças Infecciosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcefalia/embriologia , Microcefalia/virologia , Microglia/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/virologia , Carga Viral , Zika virus/fisiologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
16.
Mol Immunol ; 125: 70-82, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32652362

RESUMO

Immune responses and central nervous system dysfunction are two main factors to be considered during rabies virus (RABV) infection. However, the mechanisms by which RABV strains of different virulence regulate with chemokine expression and the signaling pathways responsible for the immune responses in the terminal stage of infection both in vivo and in vitro have not been fully elucidated. In this study, we found low expression levels of proinflammatory chemokines in the mouse brain upon infection with street RABV strains (CXZ17 and HN10) at the late stage of infection. We also examined the difference in inflammatory response upon infection with RABV strains of different virulence in a mouse model. We found that the expression of proinflammatory chemokines increased to a varying degree upon infection with street RABV (CXZ17 and HN10) or laboratory-fixed RABV (CVS-11, aG, and CTN); CXCL10, CCL5, and CCL2 were the most significantly upregulated chemokines in brain tissue and microglial BV-2 cells in response to infection with RABV strains of different virulence. Our data also demonstrate significant activation of the MAPK and NF-κB pathways in mouse brain tissue at the late stage of RABV infection. We also found (i) low phosphorylation signals of MAPK and NF-κB p65 in neuronal cells upon infection with CXZ17 and HN10 in the mouse brain and (ii) strong phosphorylation signals in cerebrovascular endothelial cells and neuronal cells upon CTN or aG infection. Moreover, we quantified the nuclear localization status of MAPK signals and NF-κB p65 upon infection with CVS-11, aG, and CTN in BV-2 cells in vitro. We also found (i) that the activation of the p38, ERK1/2, and NF-κB p65 pathway, which stimulates CXCL10, CCL5, and CCL2 expression upon infection with RABV strains of different virulence (aG, CTN, and CVS-11), is triggered after virus entry into BV-2 cells and (ii) that the expression of CXCL10, CCL5, and CCL2 is required for the activation of NF-κB, p38, and ERK1/2, but not JNK. Overall, our study provides insight into the regulation of inflammatory responses mediated by MAPK and NF-κB in the mouse brain and in microglial cells upon RABV infection of different virulence.


Assuntos
Encéfalo/virologia , Inflamação/virologia , Sistema de Sinalização das MAP Quinases/imunologia , NF-kappa B/imunologia , Vírus da Raiva/patogenicidade , Raiva/imunologia , Animais , Encéfalo/imunologia , Inflamação/imunologia , Camundongos , Microglia/imunologia , Microglia/virologia , Vírus da Raiva/imunologia , Virulência/imunologia
17.
J Infect Dis ; 222(10): 1745-1755, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32498080

RESUMO

Neurological signs and symptoms are the most common complications of Ebola virus disease. However, the mechanisms underlying the neurologic manifestations in Ebola patients are not known. In this study, peripheral ganglia were collected from 12 rhesus macaques that succumbed to Ebola virus (EBOV) disease from 5 to 8 days post exposure. Ganglionitis, characterized by neuronal degeneration, necrosis, and mononuclear leukocyte infiltrates, was observed in the dorsal root, autonomic, and enteric ganglia. By immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, we confirmed that CD68+ macrophages are the target cells for EBOV in affected ganglia. Further, we demonstrated that EBOV can induce satellite cell and neuronal apoptosis and microglial activation in infected ganglia. Our results demonstrate that EBOV can infect peripheral ganglia and results in ganglionopathy in rhesus macaques, which may contribute to the neurological signs and symptoms observed in acute and convalescent Ebola virus disease in human patients.


Assuntos
Doença pelo Vírus Ebola/complicações , Doença pelo Vírus Ebola/patologia , Degeneração Neural/complicações , Degeneração Neural/patologia , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/patologia , Animais , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Modelos Animais de Doenças , Ebolavirus , Feminino , Gânglios , Gânglios Espinais/patologia , Gânglios Espinais/virologia , Cistos Glanglionares/patologia , Doença pelo Vírus Ebola/virologia , Humanos , Imuno-Histoquímica , Leucócitos Mononucleares , Macaca mulatta , Macrófagos/patologia , Masculino , Microglia/patologia , Microglia/virologia , Necrose , Sistema Nervoso Parassimpático/patologia , Doenças do Sistema Nervoso Periférico/virologia , Células Receptoras Sensoriais/patologia , Células Receptoras Sensoriais/virologia , Sistema Nervoso Simpático/patologia
18.
Cell Mol Life Sci ; 77(24): 5079-5099, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32577796

RESUMO

Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) is a potent mediator involved in the development of HIV-1-associated neurocognitive disorders (HAND). Tat is expressed even in the presence of antiretroviral therapy (ART) and is able to enter the central nervous system (CNS) through a variety of ways, where Tat can interact with microglia, astrocytes, brain microvascular endothelial cells, and neurons. The presence of low concentrations of extracellular Tat alone has been shown to lead to dysregulated gene expression, chronic cell activation, inflammation, neurotoxicity, and structural damage in the brain. The reported effects of Tat are dependent in part on the specific HIV-1 subtype and amino acid length of Tat used. HIV-1 subtype B Tat is the most common subtype in North American and therefore, most studies have been focused on subtype B Tat; however, studies have shown many genetic, biologic, and pathologic differences between HIV subtype B and subtype C Tat. This review will focus primarily on subtype B Tat where the full-length protein is 101 amino acids, but will also consider variants of Tat, such as Tat 72 and Tat 86, that have been reported to exhibit a number of distinctive activities with respect to mediating CNS damage and neurotoxicity.


Assuntos
Complexo AIDS Demência/genética , Sistema Nervoso Central/patologia , Infecções por HIV/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Complexo AIDS Demência/patologia , Complexo AIDS Demência/terapia , Terapia Antirretroviral de Alta Atividade , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/virologia , Sistema Nervoso Central/virologia , Regulação Viral da Expressão Gênica/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , Humanos , Microglia/metabolismo , Microglia/patologia , Microglia/virologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/virologia
19.
Sci Immunol ; 5(48)2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503876

RESUMO

The neuroepithelium is a nasal barrier surface populated by olfactory sensory neurons that detect odorants in the airway and convey this information directly to the brain via axon fibers. This barrier surface is especially vulnerable to infection, yet respiratory infections rarely cause fatal encephalitis, suggesting a highly evolved immunological defense. Here, using a mouse model, we sought to understand the mechanism by which innate and adaptive immune cells thwart neuroinvasion by vesicular stomatitis virus (VSV), a potentially lethal virus that uses olfactory sensory neurons to enter the brain after nasal infection. Fate-mapping studies demonstrated that infected central nervous system (CNS) neurons were cleared noncytolytically, yet specific deletion of major histocompatibility complex class I (MHC I) from these neurons unexpectedly had no effect on viral control. Intravital imaging studies of calcium signaling in virus-specific CD8+ T cells revealed instead that brain-resident microglia were the relevant source of viral peptide-MHC I complexes. Microglia were not infected by the virus but were found to cross-present antigen after acquisition from adjacent neurons. Microglia depletion interfered with T cell calcium signaling and antiviral control in the brain after nasal infection. Collectively, these data demonstrate that microglia provide a front-line defense against a neuroinvasive nasal infection by cross-presenting antigen to antiviral T cells that noncytolytically cleanse neurons. Disruptions in this innate defense likely render the brain susceptible to neurotropic viruses like VSV that attempt to enter the CNS via the nose.


Assuntos
Apresentação do Antígeno/imunologia , Encéfalo/imunologia , Linfócitos T CD8-Positivos/imunologia , Microglia/imunologia , Células Neuroepiteliais/imunologia , Nariz/virologia , Estomatite Vesicular/imunologia , Animais , Encéfalo/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/virologia , Células Neuroepiteliais/virologia , Estomatite Vesicular/virologia
20.
Viruses ; 12(5)2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32443728

RESUMO

Even with an efficient combination of antiretroviral therapy (ART), which significantly decreases viral load in human immunodeficiency virus type 1 (HIV-1)-positive individuals, the occurrence of HIV-1-associated neurocognitive disorders (HAND) still exists. Microglia have been shown to have a significant role in HIV-1 replication in the brain and in subsequent HAND pathogenesis. However, due to the limited ability of ART drugs to cross the blood-brain barrier (BBB) after systemic administration, in addition to efflux transporter expression on microglia, the efficacy of ART drugs for viral suppression in microglia is suboptimal. Previously, we developed novel poly (lactic-co-glycolic acid) (PLGA)-based elvitegravir nanoparticles (PLGA-EVG NPs), which showed improved BBB penetration in vitro and improved viral suppression in HIV-1-infected primary macrophages, after crossing an in vitro BBB model. Our objective in the current study was to evaluate the efficacy of our PLGA-EVG NPs in an important central nervous system (CNS) HIV-1 reservoir, i.e., microglia. In this study, we evaluated the cyto-compatibility of the PLGA-EVG NPs in microglia, using an XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and cellular morphology observation. We also studied the endocytosis pathway and the subcellular localization of PLGA NPs in microglia, using various endocytosis inhibitors and subcellular localization markers. We determined the ability of PLGA-EVG NPs to suppress HIV-1 replication in microglia, after crossing an in vitro BBB model. We also studied the drug levels in mouse plasma and brain tissue, using immunodeficient NOD scid gamma (NSG) mice, and performed a pilot study, to evaluate the efficacy of PLGA-EVG NPs on viral suppression in the CNS, using an HIV-1 encephalitic (HIVE) mouse model. From our results, the PLGA-EVG NPs showed ~100% biocompatibility with microglia, as compared to control cells. The internalization of PLGA NPs in microglia occurred through caveolae-/clathrin-mediated endocytosis. PLGA NPs can also escape from endo-lysosomal compartments and deliver the therapeutics to cells efficiently. More importantly, the PLGA-EVG NPs were able to show ~25% more viral suppression in HIV-1-infected human-monocyte-derived microglia-like cells after crossing the in vitro BBB compared to the EVG native drug, without altering BBB integrity. PLGA-EVG NPs also showed a ~two-fold higher level in mouse brain and a trend of decreasing CNS HIV-1 viral load in HIV-1-infected mice. Overall, these results help us to create a safe and efficient drug delivery method to target HIV-1 reservoirs in the CNS, for potential clinical use.


Assuntos
Fármacos Anti-HIV/farmacologia , Antirretrovirais/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Inibidores de Integrase/farmacologia , Microglia/virologia , Replicação Viral/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Infecções por HIV/tratamento farmacológico , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Nanopartículas/química , Projetos Piloto , Plasma/virologia , Quinolonas/farmacologia , Carga Viral
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