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1.
Nat Commun ; 11(1): 5207, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060630

RESUMO

Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. Moreover, FN-vlPAG projections also modulate extinction learning. We also found a FN-parafascicular thalamus pathway, which may relay cerebellar influence to the amygdala and modulates anxiety behaviors. Overall, our results reveal multiple contributions of the cerebellum to the emotional system.


Assuntos
Sistema Nervoso Central/fisiologia , Medo/fisiologia , Memória/fisiologia , Vias Neurais/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Sistema Nervoso Central/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Aprendizagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Optogenética
2.
Int J Mol Sci ; 21(18)2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32971906

RESUMO

In December 2019, physicians reported numerous patients showing pneumonia of unknown origin in the Chinese region of Wuhan. Following the spreading of the infection over the world, The World Health Organization (WHO) on 11 March 2020 declared the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak a global pandemic. The scientific community is exerting an extraordinary effort to elucidate all aspects related to SARS-CoV-2, such as the structure, ultrastructure, invasion mechanisms, replication mechanisms, or drugs for treatment, mainly through in vitro studies. Thus, the clinical in vivo data can provide a test bench for new discoveries in the field of SARS-CoV-2, finding new solutions to fight the current pandemic. During this dramatic situation, the normal scientific protocols for the development of new diagnostic procedures or drugs are frequently not completely applied in order to speed up these processes. In this context, interdisciplinarity is fundamental. Specifically, a great contribution can be provided by the association and interpretation of data derived from medical disciplines based on the study of images, such as radiology, nuclear medicine, and pathology. Therefore, here, we highlighted the most recent histopathological and imaging data concerning the SARS-CoV-2 infection in lung and other human organs such as the kidney, heart, and vascular system. In addition, we evaluated the possible matches among data of radiology, nuclear medicine, and pathology departments in order to support the intense scientific work to address the SARS-CoV-2 pandemic. In this regard, the development of artificial intelligence algorithms that are capable of correlating these clinical data with the new scientific discoveries concerning SARS-CoV-2 might be the keystone to get out of the pandemic.


Assuntos
Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Inteligência Artificial , Betacoronavirus/isolamento & purificação , Sistema Nervoso Central/patologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Rim/patologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Miocárdio/patologia , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Prognóstico , Pele/patologia
3.
Scand J Immunol ; 92(5): e12963, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32851668

RESUMO

Myeloid cells represent the major cellular component of innate immune responses. Myeloid cells include monocytes and macrophages, granulocytes (neutrophils, basophils and eosinophils) and dendritic cells (DC). The role of myeloid cells has been broadly described both in physiological and in pathological conditions. All tissues or organs are equipped with resident myeloid cells, such as parenchymal microglia in the brain, which contribute to maintaining homeostasis. Moreover, in case of infection or tissue damage, other myeloid cells such as monocytes or granulocytes (especially neutrophils) can be recruited from the circulation, at first to promote inflammation and later to participate in repair and regeneration. This review aims to address the regulatory roles of myeloid cells in inflammatory diseases of the central nervous system (CNS), with a particular focus on recent work showing induction of suppressive function via stimulation of innate signalling in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE).


Assuntos
Sistema Nervoso Central/imunologia , Células Dendríticas/imunologia , Granulócitos/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Células Mieloides/imunologia , Animais , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia
4.
Future Microbiol ; 15: 1287-1305, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32851877

RESUMO

Aim: Despite the similarities in the pathogenesis of the beta coronaviruses, the precise infective mechanisms of SARS-CoV-2 remain unclear. Objective: In this review, we aim to focus on the proposed theories behind the pathogenesis of SARS-CoV-2 and highlight the clinical complications related to COVID-19. Methods: We conducted a literature search in Pubmed, Scopus and Google Scholar for the relevant articles regarding clinical complications and pathogenesis of COVID-19. Results: Related articles were included and discussed. Conclusion: Respiratory system and the lungs are the most commonly involved sites of COVID-19 infection. Cardiovascular, liver, kidneys, gastrointestinal and central nervous systems are involved with different frequencies and degrees of severity.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Sistema Cardiovascular/patologia , Sistema Cardiovascular/virologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/transmissão , Citocinas/sangue , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Humanos , Rim/patologia , Rim/virologia , Fígado/patologia , Fígado/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/transmissão , Sistema Respiratório/patologia , Sistema Respiratório/virologia
5.
Indian J Med Res ; 152(1 & 2): 41-47, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32859864

RESUMO

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been predominantly a respiratory manifestation. Currently, with evolving literature, neurological signs are being increasingly recognized. Studies have reported that SARS-CoV-2 affects all aspects of the nervous system including the central nervous system (CNS), peripheral nervous system (PNS) and the muscular system as well. Not all patients have reverse transcription-polymerase chain reaction positive for the virus in the cerebrospinal fluid, and diagnosing the association of the virus with the myriad of neurological manifestations can be a challenge. It is important that clinicians have a high-index of suspicion for COVID-19 in patients presenting with new-onset neurological symptoms. This will lead to early diagnosis and specific management. Further studies are desired to unravel the varied neurological manifestations, treatment, outcome and long-term sequel in COVID-19 patients.


Assuntos
Sistema Nervoso Central/patologia , Infecções por Coronavirus/epidemiologia , Doenças do Sistema Nervoso/epidemiologia , Sistema Nervoso Periférico/patologia , Pneumonia Viral/epidemiologia , Betacoronavirus/patogenicidade , Sistema Nervoso Central/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Músculo Esquelético/patologia , Músculo Esquelético/virologia , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/virologia , Pandemias , Sistema Nervoso Periférico/virologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia
6.
PLoS One ; 15(7): e0219632, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706829

RESUMO

INTRODUCTION: Surgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy. METHODS: The development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells. RESULTS: The DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment. CONCLUSIONS: These findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Hidrogéis/química , Paclitaxel/uso terapêutico , Peptídeos/química , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Sistema Nervoso Central/patologia , Portadores de Fármacos/química , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Paclitaxel/química , Taxa de Sobrevida , Temozolomida/química , Temozolomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
7.
DNA Cell Biol ; 39(8): 1449-1457, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32609007

RESUMO

Kearns-Sayre Syndrome (KSS) is a severe mitochondrial disorder involving the central nervous system, eyes, ears, skeletal muscles, and heart. The mitochondrial DNA (mtDNA) rearrangements, especially the deletions, are present in almost all KSS patients and considered as the disease-causing factor. However, the size and position of mtDNA deletions are distinct in different individuals. In this study, we report the case of a pair of Chinese twins with KSS. The twin patients revealed typical KSS clinical symptoms, including heart block, bilateral sensorineural hearing loss, progressive external ophthalmoplegia, exercise intolerance, proximal limb weakness, and endocrine disorders. Using long-range polymerase chain reactions (long-range PCR) and next-generation sequencing (NGS), the genetic features of the twin patients were investigated. A large 6600 bp mtDNA deletion, ranging from position 8702 to 15,302, was detected in both patients. To our knowledge, this kind of mtDNA deletion has never been described previously. Our study enriched the mutation spectrum of KSS and showed that NGS is a powerful tool for detecting mtDNA large variants.


Assuntos
DNA Mitocondrial/genética , Doenças em Gêmeos/genética , Síndrome de Kearns-Sayre/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Sistema Nervoso Central/patologia , Criança , Cromossomos/genética , Doenças em Gêmeos/patologia , Orelha/patologia , Olho/patologia , Deleção de Genes , Predisposição Genética para Doença , Coração/fisiopatologia , Humanos , Síndrome de Kearns-Sayre/patologia , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação/genética , Oftalmoplegia Externa Progressiva Crônica/patologia , Fenótipo
9.
J Neurovirol ; 26(3): 324-329, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32418055

RESUMO

Coronavirus disease 2019 (COVID-19) was reported at the end of 2019 in China for the first time and has rapidly spread throughout the world as a pandemic. Since COVID-19 causes mild to severe acute respiratory syndrome, most studies in this field have only focused on different aspects of pathogenesis in the respiratory system. However, evidence suggests that COVID-19 may affect the central nervous system (CNS). Given the outbreak of COVID-19, it seems necessary to perform investigations on the possible neurological complications in patients who suffered from COVID-19. Here, we reviewed the evidence of the neuroinvasive potential of coronaviruses and discussed the possible pathogenic processes in CNS infection by COVID-19 to provide a precise insight for future studies.


Assuntos
Ataxia/epidemiologia , Edema Encefálico/epidemiologia , Infecções por Coronavirus/epidemiologia , Encefalite Viral/epidemiologia , Epilepsia/epidemiologia , Esclerose Múltipla/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Ataxia/complicações , Ataxia/diagnóstico , Ataxia/virologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/virologia , Edema Encefálico/complicações , Edema Encefálico/diagnóstico , Edema Encefálico/virologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Encefalite Viral/complicações , Encefalite Viral/diagnóstico , Encefalite Viral/virologia , Epilepsia/complicações , Epilepsia/diagnóstico , Epilepsia/virologia , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/virologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão , Prevalência , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/diagnóstico , Síndrome Respiratória Aguda Grave/transmissão
10.
J Clin Neurosci ; 78: 439-443, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32387256

RESUMO

Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare benign lesions that can arise anywhere within the central nervous system. The etiology of these lesions remains unknown and diagnosis is made on pathohistological analysis. We present the case of a 35-year-old male patient with a history of epilepsy since childhood who was evaluated for refractory seizures. MRI revealed a small lesion in the left-posterior temporal lobe suspected to be a cavernoma. A gross total resection of the lesion was achieved via a left temporal craniotomy and pathological analysis revealed CAPNON. At 6 months follow-up, the patient remained neurologically intact and his seizures had ceased.


Assuntos
Calcinose/patologia , Sistema Nervoso Central/patologia , Convulsões/etiologia , Adulto , Calcinose/complicações , Calcinose/diagnóstico por imagem , Cefalometria , Humanos , Imagem por Ressonância Magnética , Masculino , Lobo Temporal/patologia , Lobo Temporal/cirurgia , Resultado do Tratamento
11.
PLoS One ; 15(5): e0227463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469979

RESUMO

Disruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis including fluctuations of pH occurs during cortical spreading depression (CSD) events associated with several neurological disorders, including migraine with aura, traumatic brain injury and stroke. NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total expression of NHE1 in cortex and PAG but increased expression in trigeminal ganglia; no changes were seen in trigeminal nucleus caudalis. Thus, in vitro observations may have a significance in vivo to increase brain sumatriptan levels. Pharmacological inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the antimigraine agent, sumatriptan.


Assuntos
Barreira Hematoencefálica/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical/genética , Trocador 1 de Sódio-Hidrogênio/genética , Sumatriptana/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Enxaqueca com Aura/tratamento farmacológico , Enxaqueca com Aura/genética , Enxaqueca com Aura/patologia , Ratos , Trocador 1 de Sódio-Hidrogênio/antagonistas & inibidores , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/patologia
12.
PLoS Pathog ; 16(5): e1008204, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32357162

RESUMO

Zika virus (ZIKV) can infect and cause microcephaly and Zika-associated neurological complications in the developing fetal and adult brains. In terms of pathogenesis, a critical question is how ZIKV overcomes the barriers separating the brain from the circulation and gains access to the central nervous system (CNS). Despite the importance of ZIKV pathogenesis, the route ZIKV utilizes to cross CNS barriers remains unclear. Here we show that in mouse models, ZIKV-infected cells initially appeared in the periventricular regions of the brain, including the choroid plexus and the meninges, prior to infection of the cortex. The appearance of ZIKV in cerebrospinal fluid (CSF) preceded infection of the brain parenchyma. Further the brain infection was significantly attenuated by neutralization of the virus in the CSF, indicating that ZIKV in the CSF at the early stage of infection might be responsible for establishing a lethal infection of the brain. We show that cells infected by ZIKV in the choroid plexus were pericytes. Using in vitro systems, we highlight the possibility that ZIKV crosses the blood-CSF barrier by disrupting the choroid plexus epithelial layer. Taken together, our results suggest that ZIKV might exploit the blood-CSF barrier rather than the blood-brain barrier to invade the CNS.


Assuntos
Plexo Corióideo/patologia , Pericitos/patologia , Infecção por Zika virus/patologia , Animais , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Sistema Nervoso Central/patologia , Chlorocebus aethiops , Plexo Corióideo/metabolismo , Plexo Corióideo/virologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcefalia/complicações , Microcefalia/virologia , Doenças do Sistema Nervoso , Pericitos/metabolismo , Pericitos/virologia , Cultura Primária de Células , Células Vero , Zika virus/fisiologia , Infecção por Zika virus/virologia
13.
J Med Virol ; 92(7): 786-790, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-102134

RESUMO

An outbreak of a novel coronavirus (SARS-CoV-2) infection has recently emerged and rapidly spreading in humans causing a significant threat to international health and the economy. Rapid assessment and warning are crucial for an outbreak analysis in response to serious public health. SARS-CoV-2 shares highly homological sequences with SARS-CoVs causing highly lethal pneumonia with respiratory distress and clinical symptoms similar to those reported for SARS-CoV and MERS-CoV infections. Notably, some COVID-19 patients also expressed neurologic signs like nausea, headache, and vomiting. Several studies have reported that coronaviruses are not only causing respiratory illness but also invade the central nervous system through a synapse-connected route. SARS-CoV infections are reported in both patients and experimental animals' brains. Interestingly, some COVID-19 patients have shown the presence of SARS-CoV-2 virus in their cerebrospinal fluid. Considering the similarities between SARS-CoV and SARS-CoV-2 in various aspects, it remains to clarify whether the potent invasion of SARS-CoV-2 may affect in COVID-19 patients. All these indicate that more detailed criteria are needed for the treatment and the prevention of SARS-CoV-2 infected patients. In the absence of potential interventions for COVID-19, there is an urgent need for an alternative strategy to control the spread of this disease.


Assuntos
Betacoronavirus/patogenicidade , Sistema Nervoso Central/virologia , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Antivirais/uso terapêutico , Betacoronavirus/genética , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Cefaleia/diagnóstico , Cefaleia/fisiopatologia , Cefaleia/virologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Náusea/diagnóstico , Náusea/fisiopatologia , Náusea/virologia , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Saúde Pública/métodos , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/diagnóstico , Síndrome Respiratória Aguda Grave/prevenção & controle , Síndrome Respiratória Aguda Grave/virologia , Vacinas Virais/biossíntese , Vacinas Virais/uso terapêutico , Vômito/diagnóstico , Vômito/fisiopatologia , Vômito/virologia
16.
mBio ; 11(2)2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317323

RESUMO

Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4+ T cells (CD4) and macrophages (MΦs) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4+ memory T cells (Br-mCD4), brain-MΦs (Br-MΦs), and brain B cells (Br-B cells). Both Br-mCD4s and Br-MΦs harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-MΦs. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain.IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4+ T cells harbor replication-competent SIV DNA; however, only brain CD4+ T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Macrófagos/imunologia , Doenças do Sistema Nervoso/etiologia , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Biomarcadores , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Modelos Animais de Doenças , Imunofluorescência , Imuno-Histoquímica , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Macrófagos/metabolismo , Macrófagos/virologia , Doenças do Sistema Nervoso/patologia , Neuroimunomodulação , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Carga Viral , Virulência
17.
PLoS One ; 15(4): e0228771, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32255788

RESUMO

Hyperphosphorylated tau protein is a pathological hallmark of numerous neurodegenerative diseases and the level of tau pathology is correlated with the degree of cognitive impairment. Tau hyper-phosphorylation is thought to be an early initiating event in the cascade leading to tau toxicity and neuronal death. Inhibition of tau phosphorylation therefore represents an attractive therapeutic strategy. However, the widespread expression of most kinases and promiscuity of their substrates, along with poor selectivity of most kinase inhibitors, have resulted in systemic toxicities that have limited the advancement of tau kinase inhibitors into the clinic. We therefore focused on the CNS-specific tau kinase, TTBK1, and investigated whether selective inhibition of this kinase could represent a viable approach to targeting tau phosphorylation in disease. In the current study, we demonstrate that TTBK1 regulates tau phosphorylation using overexpression or knockdown of this kinase in heterologous cells and primary neurons. Importantly, we find that TTBK1-specific phosphorylation of tau leads to a loss of normal protein function including a decrease in tau-tubulin binding and deficits in tubulin polymerization. We then describe the use of a novel, selective small molecule antagonist, BIIB-TTBK1i, to study the acute effects of TTBK1 inhibition on tau phosphorylation in vivo. We demonstrate substantial lowering of tau phosphorylation at multiple sites implicated in disease, suggesting that TTBK1 inhibitors may represent an exciting new approach in the search for neurodegenerative disease therapies.


Assuntos
Doenças do Sistema Nervoso Central/enzimologia , Doenças do Sistema Nervoso Central/patologia , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas tau/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos Endogâmicos C57BL , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Especificidade de Órgãos , Fosforilação/efeitos dos fármacos , Polimerização , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Tubulina (Proteína)/metabolismo
18.
PLoS One ; 15(4): e0226050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240164

RESUMO

Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80+ CD11b+ cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.


Assuntos
Encefalomielite Autoimune Experimental/genética , Lisofosfolipídeos/genética , Esclerose Múltipla/genética , Diester Fosfórico Hidrolases/genética , Animais , Antígeno CD11b/genética , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/fisiopatologia , Deleção de Genes , Expressão Gênica/genética , Humanos , Lisofosfolipídeos/biossíntese , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Esclerose Múltipla/sangue , Esclerose Múltipla/fisiopatologia , Transdução de Sinais/genética , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
19.
Rinsho Shinkeigaku ; 60(5): 351-357, 2020 May 26.
Artigo em Japonês | MEDLINE | ID: mdl-32307398

RESUMO

The patient was a 40-year-old woman who was previously diagnosed with systemic lupus erythematosus and myasthenia gravis and had received prednisolone and tacrolimus for more than 7 years. In February 2017, she noticed pain in her lower back and weakness of the lower limbs, and was referred to our hospital on day 5. She had shingles in the right lower thoracic dermatomes and Brown-Séquard syndrome with right-sided dominant weakness in her lower limbs and left-sided superficial sensory disturbance below the L1 level. Varicella zoster virus (VZV)-associated myelopathy was suspected because of her symptoms and clinical findings. Despite the immediate administration of intravenous acyclovir after hospitalization, she lost consciousness and experienced a seizure related to cerebral hemorrhage in the left temporal lobe on the night of day 5. MRI showed enhanced lesions along the spinal cord and leptomeninges of the brainstem and temporal lobe. VZV-IgG and VZV-DNA were positive in the cerebrospinal fluid. Based on these clinical features and laboratory findings, she was diagnosed as VZV-associated vasculopathy and myelopathy. She subsequently had multiple cerebral infractions and hemorrhage, and developed sudden cardiopulmonary arrest on day 6, culminating in death on day 17. Autopsy showed that inflammatory mononuclear cells had infiltrated the vascular walls of the spinal cord. Immunohistochemistry revealed that some neurons and macrophages in the white matter of the spinal cord were positive for VZV. In addition, atrophic neurons, satellite cells surrounding these neurons, and infiltrating macrophages were immune-positive for VZV at the L2 dorsal root ganglia. These findings were consistent with VZV-associated vasculopathy and myelitis. Under immunosuppressive conditions, VZV can cause shingles and neuronal complications such as vasculopathy and myelitis, which are sometimes fatal despite the immediate administration of intravenous acyclovir. New treatment drugs or drugs to prevent VZV activation are desired.


Assuntos
Encefalite por Varicela Zoster/diagnóstico , Encefalite por Varicela Zoster/etiologia , Encefalite Viral/diagnóstico , Encefalite Viral/etiologia , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Prednisolona/efeitos adversos , Tacrolimo/efeitos adversos , Adulto , Autopsia , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Encefalite por Varicela Zoster/patologia , Encefalite por Varicela Zoster/virologia , Encefalite Viral/patologia , Encefalite Viral/virologia , Evolução Fatal , Feminino , Humanos , Imagem por Ressonância Magnética , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
20.
J Med Virol ; 92(7): 786-790, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32320066

RESUMO

An outbreak of a novel coronavirus (SARS-CoV-2) infection has recently emerged and rapidly spreading in humans causing a significant threat to international health and the economy. Rapid assessment and warning are crucial for an outbreak analysis in response to serious public health. SARS-CoV-2 shares highly homological sequences with SARS-CoVs causing highly lethal pneumonia with respiratory distress and clinical symptoms similar to those reported for SARS-CoV and MERS-CoV infections. Notably, some COVID-19 patients also expressed neurologic signs like nausea, headache, and vomiting. Several studies have reported that coronaviruses are not only causing respiratory illness but also invade the central nervous system through a synapse-connected route. SARS-CoV infections are reported in both patients and experimental animals' brains. Interestingly, some COVID-19 patients have shown the presence of SARS-CoV-2 virus in their cerebrospinal fluid. Considering the similarities between SARS-CoV and SARS-CoV-2 in various aspects, it remains to clarify whether the potent invasion of SARS-CoV-2 may affect in COVID-19 patients. All these indicate that more detailed criteria are needed for the treatment and the prevention of SARS-CoV-2 infected patients. In the absence of potential interventions for COVID-19, there is an urgent need for an alternative strategy to control the spread of this disease.


Assuntos
Betacoronavirus/patogenicidade , Sistema Nervoso Central/virologia , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Antivirais/uso terapêutico , Betacoronavirus/genética , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Cefaleia/diagnóstico , Cefaleia/fisiopatologia , Cefaleia/virologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Náusea/diagnóstico , Náusea/fisiopatologia , Náusea/virologia , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Saúde Pública/métodos , Vírus da SARS/genética , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/diagnóstico , Síndrome Respiratória Aguda Grave/prevenção & controle , Síndrome Respiratória Aguda Grave/virologia , Vacinas Virais/biossíntese , Vacinas Virais/uso terapêutico , Vômito/diagnóstico , Vômito/fisiopatologia , Vômito/virologia
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