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1.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207166

RESUMO

Rabies virus (RABV) induces acute, fatal encephalitis in mammals including humans. The circRNAs are important in virus infection process, but whether circRNAs regulated RABV infection remains largely unknown. Here, mice brain with or without the RABV CVS-11 strain were subjected to RNA sequencing and a total of 30,985 circRNAs were obtained. Among these, 9021 candidates were shared in both groups, and 14,610 and 7354 circRNAs were expressed specifically to the control and experimental groups, indicating that certain circRNAs were specifically inhibited or induced on RABV infection. The circRNAs mainly derived from coding exons. In total, 636 circRNAs were differentially expressed in RABV infection, of which 426 significantly upregulated and 210 significantly downregulated (p < 0.05 and fold change ≥2). The expression of randomly selected 6 upregulated and 6 downregulated circRNAs was tested by RT-qPCR, and the expression trend of the 11 out of 12 circRNAs was consistent in RT- qPCR and RNA-seq analysis. Rnase R-resistant assay and Sanger sequencing were conducted to verify the circularity of circRNAs. GO analysis demonstrated that source genes of all differentially regulated circRNAs were mainly related to cell plasticity and synapse function. Both KEGG and GSEA analysis revealed that these source genes were engaged in the cGMP-PKG and MAPK signaling pathway, and HTLV-I infection. Also, pathways related to glucose metabolism and synaptic functions were enriched in KEGG analysis. The circRNA-miRNA-mRNA network was built with 25 of 636 differentially expressed circRNAs, 264 mRNAs involved in RABV infection, and 29 miRNAs. Several miRNAs and many mRNAs in the network were reported to be related to viral infection and the immune response, suggesting that circRNAs could regulate RABV infection via interacting with miRNAs and mRNAs. Taken together, this study first characterized the transcriptomic pattern of circRNAs, and signaling pathways and function that circRNAs are involved in, which may indicate directions for further research to understand mechanisms of RABV pathogenesis.


Assuntos
Encéfalo/metabolismo , Encéfalo/virologia , Biologia Computacional , Perfilação da Expressão Gênica , RNA Circular , Vírus da Raiva , Raiva/genética , Raiva/virologia , Animais , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno/genética , Camundongos , MicroRNAs/genética , Interferência de RNA , RNA Mensageiro/genética , Vírus da Raiva/fisiologia , Transcriptoma
2.
PLoS Pathog ; 17(5): e1009585, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34010360

RESUMO

Coronavirus disease-19 (COVID-19) emerged in late 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and may have infected an intermediate host prior to spillover into humans. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 6 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood-brain barrier. Despite this, no conspicuous signs of disease were observed, and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, including IFNα, IFNß, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8ß expression in the lungs was concomitant with Tbx21, IFNγ and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission and localization into the olfactory bulb, recapitulating human neuropathology. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources determined the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 respiratory disease and neuropathogenesis, and that they have the potential to serve as secondary reservoir hosts in North America.


Assuntos
COVID-19/fisiopatologia , COVID-19/transmissão , Peromyscus/virologia , Doenças dos Roedores/transmissão , Animais , Encéfalo/patologia , Encéfalo/virologia , COVID-19/patologia , Modelos Animais de Doenças , Reservatórios de Doenças , Suscetibilidade a Doenças , Feminino , Masculino , Doenças dos Roedores/patologia , Doenças dos Roedores/virologia , Glicoproteína da Espícula de Coronavírus/genética , Replicação Viral
4.
J Gen Virol ; 102(5)2021 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1219293

RESUMO

SARS-CoV-2 is the causative agent of COVID-19 and human infections have resulted in a global health emergency. Small animal models that reproduce key elements of SARS-CoV-2 human infections are needed to rigorously screen candidate drugs to mitigate severe disease and prevent the spread of SARS-CoV-2. We and others have reported that transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the Keratin 18 (K18) promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge. Here we report that some infected mice that survive challenge have residual pulmonary damages and persistent brain infection on day 28 post-infection despite the presence of anti-SARS-COV-2 neutralizing antibodies. Because of the hypersensitivity of K18-hACE2 mice to SARS-CoV-2 and the propensity of virus to infect the brain, we sought to determine if anti-infective biologics could protect against disease in this model system. We demonstrate that anti-SARS-CoV-2 human convalescent plasma protects K18-hACE2 against severe disease. All control mice succumbed to disease by day 7; however, all treated mice survived infection without observable signs of disease. In marked contrast to control mice, viral antigen and lesions were reduced or absent from lungs and absent in brains of antibody-treated mice. Our findings support the use of K18-hACE2 mice for protective efficacy studies of anti-SARS-CoV-2 medical countermeasures (MCMs). They also support the use of this system to study SARS-CoV-2 persistence and host recovery.


Assuntos
COVID-19/terapia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/virologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Encéfalo/patologia , Encéfalo/virologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Modelos Animais de Doenças , Feminino , Humanos , Imunização Passiva , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Coronavírus/genética , Receptores de Coronavírus/metabolismo , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Carga Viral , Replicação Viral
5.
PLoS Pathog ; 17(5): e1009585, 2021 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1234597

RESUMO

Coronavirus disease-19 (COVID-19) emerged in late 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and may have infected an intermediate host prior to spillover into humans. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 6 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood-brain barrier. Despite this, no conspicuous signs of disease were observed, and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, including IFNα, IFNß, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8ß expression in the lungs was concomitant with Tbx21, IFNγ and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission and localization into the olfactory bulb, recapitulating human neuropathology. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources determined the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 respiratory disease and neuropathogenesis, and that they have the potential to serve as secondary reservoir hosts in North America.


Assuntos
COVID-19/fisiopatologia , COVID-19/transmissão , Peromyscus/virologia , Doenças dos Roedores/transmissão , Animais , Encéfalo/patologia , Encéfalo/virologia , COVID-19/patologia , Modelos Animais de Doenças , Reservatórios de Doenças , Suscetibilidade a Doenças , Feminino , Masculino , Doenças dos Roedores/patologia , Doenças dos Roedores/virologia , Glicoproteína da Espícula de Coronavírus/genética , Replicação Viral
6.
Front Immunol ; 12: 665300, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1226978

RESUMO

The irruption of SARS-CoV-2 during 2020 has been of pandemic proportions due to its rapid spread and virulence. COVID-19 patients experience respiratory, digestive and neurological symptoms. Distinctive symptom as anosmia, suggests a potential neurotropism of this virus. Amongst the several pathways of entry to the nervous system, we propose an alternative pathway from the infection of the gut, involving Toll-like receptor 4 (TLR4), zonulin, protease-activated receptor 2 (PAR2) and zonulin brain receptor. Possible use of zonulin antagonists could be investigated to attenuate neurological manifestations caused by SARS-CoV-19 infection.


Assuntos
COVID-19/complicações , Haptoglobinas/metabolismo , Doenças do Sistema Nervoso/complicações , Precursores de Proteínas/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Encéfalo/metabolismo , Encéfalo/virologia , COVID-19/metabolismo , COVID-19/virologia , Proteínas do Sistema Complemento/metabolismo , Gastroenteropatias/complicações , Gastroenteropatias/metabolismo , Gastroenteropatias/virologia , Humanos , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/virologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Receptor 4 Toll-Like/metabolismo
7.
Acta Neurobiol Exp (Wars) ; 81(1): 69-79, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1190720

RESUMO

The recent pandemic of the coronavirus infectious disease 2019 (COVID-19) has affected around 192 countries, and projections have shown that around 40% to 70% of world population could be infected in the next months. COVID-19 is caused by the virus SARS- CoV-2, it enters the cells through the ACE2 receptor (angiotensin converting enzyme 2). It is well known that SARS-CoV-2 could develop mild, moderate, and severe respiratory symptoms that could lead to death. The virus receptor is expressed in different organs such as the lungs, kidney, intestine, and brain, among others. In the lung could cause pneumonia and severe acute respiratory syndrome (SARS). The brain can be directly affected by cellular damage due to viral invasion, which can lead to an inflammatory response, by the decrease in the enzymatic activity of ACE2 that regulates neuroprotective, neuro-immunomodulatory and neutralizing functions of oxidative stress. Another severe damage is hypoxemia in patients that do not receive adequate respiratory support. The neurological symptoms that the patient presents, will depend on factors that condition the expression of ACE2 in the brain such as age and sex, as well as the mechanism of neuronal invasion, the immune response and the general state of the patient. Clinical and histopathological studies have described neurological alterations in human patients with COVID-19. These conditions could have a possible contribution to the morbidity and mortality caused by this disease and may even represent the onset of neurodegenerative activity in recovered patients.The recent pandemic of the coronavirus infectious disease 2019 (COVID-19) has affected around 192 countries, and projections have shown that around 40% to 70% of world population could be infected in the next months. COVID-19 is caused by the virus SARS- CoV-2, it enters the cells through the ACE2 receptor (angiotensin converting enzyme 2). It is well known that SARS-CoV-2 could develop mild, moderate, and severe respiratory symptoms that could lead to death. The virus receptor is expressed in different organs such as the lungs, kidney, intestine, and brain, among others. In the lung could cause pneumonia and severe acute respiratory syndrome (SARS). The brain can be directly affected by cellular damage due to viral invasion, which can lead to an inflammatory response, by the decrease in the enzymatic activity of ACE2 that regulates neuroprotective, neuro-immunomodulatory and neutralizing functions of oxidative stress. Another severe damage is hypoxemia in patients that do not receive adequate respiratory support. The neurological symptoms that the patient presents, will depend on factors that condition the expression of ACE2 in the brain such as age and sex, as well as the mechanism of neuronal invasion, the immune response and the general state of the patient. Clinical and histopathological studies have described neurological alterations in human patients with COVID-19. These conditions could have a possible contribution to the morbidity and mortality caused by this disease and may even represent the onset of neurodegenerative activity in recovered patients.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Encéfalo/virologia , COVID-19/epidemiologia , Doenças Transmissíveis/virologia , SARS-CoV-2/patogenicidade , COVID-19/virologia , Humanos , Neurônios/virologia
8.
J Gen Virol ; 102(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33961540

RESUMO

SARS-CoV-2 is the causative agent of COVID-19 and human infections have resulted in a global health emergency. Small animal models that reproduce key elements of SARS-CoV-2 human infections are needed to rigorously screen candidate drugs to mitigate severe disease and prevent the spread of SARS-CoV-2. We and others have reported that transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the Keratin 18 (K18) promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge. Here we report that some infected mice that survive challenge have residual pulmonary damages and persistent brain infection on day 28 post-infection despite the presence of anti-SARS-COV-2 neutralizing antibodies. Because of the hypersensitivity of K18-hACE2 mice to SARS-CoV-2 and the propensity of virus to infect the brain, we sought to determine if anti-infective biologics could protect against disease in this model system. We demonstrate that anti-SARS-CoV-2 human convalescent plasma protects K18-hACE2 against severe disease. All control mice succumbed to disease by day 7; however, all treated mice survived infection without observable signs of disease. In marked contrast to control mice, viral antigen and lesions were reduced or absent from lungs and absent in brains of antibody-treated mice. Our findings support the use of K18-hACE2 mice for protective efficacy studies of anti-SARS-CoV-2 medical countermeasures (MCMs). They also support the use of this system to study SARS-CoV-2 persistence and host recovery.


Assuntos
COVID-19/terapia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/virologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Encéfalo/patologia , Encéfalo/virologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Modelos Animais de Doenças , Feminino , Humanos , Imunização Passiva , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Coronavírus/genética , Receptores de Coronavírus/metabolismo , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Carga Viral , Replicação Viral
9.
Acta Neurobiol Exp (Wars) ; 81(1): 69-79, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33949163

RESUMO

The recent pandemic of the coronavirus infectious disease 2019 (COVID-19) has affected around 192 countries, and projections have shown that around 40% to 70% of world population could be infected in the next months. COVID-19 is caused by the virus SARS- CoV-2, it enters the cells through the ACE2 receptor (angiotensin converting enzyme 2). It is well known that SARS-CoV-2 could develop mild, moderate, and severe respiratory symptoms that could lead to death. The virus receptor is expressed in different organs such as the lungs, kidney, intestine, and brain, among others. In the lung could cause pneumonia and severe acute respiratory syndrome (SARS). The brain can be directly affected by cellular damage due to viral invasion, which can lead to an inflammatory response, by the decrease in the enzymatic activity of ACE2 that regulates neuroprotective, neuro-immunomodulatory and neutralizing functions of oxidative stress. Another severe damage is hypoxemia in patients that do not receive adequate respiratory support. The neurological symptoms that the patient presents, will depend on factors that condition the expression of ACE2 in the brain such as age and sex, as well as the mechanism of neuronal invasion, the immune response and the general state of the patient. Clinical and histopathological studies have described neurological alterations in human patients with COVID-19. These conditions could have a possible contribution to the morbidity and mortality caused by this disease and may even represent the onset of neurodegenerative activity in recovered patients.The recent pandemic of the coronavirus infectious disease 2019 (COVID-19) has affected around 192 countries, and projections have shown that around 40% to 70% of world population could be infected in the next months. COVID-19 is caused by the virus SARS- CoV-2, it enters the cells through the ACE2 receptor (angiotensin converting enzyme 2). It is well known that SARS-CoV-2 could develop mild, moderate, and severe respiratory symptoms that could lead to death. The virus receptor is expressed in different organs such as the lungs, kidney, intestine, and brain, among others. In the lung could cause pneumonia and severe acute respiratory syndrome (SARS). The brain can be directly affected by cellular damage due to viral invasion, which can lead to an inflammatory response, by the decrease in the enzymatic activity of ACE2 that regulates neuroprotective, neuro-immunomodulatory and neutralizing functions of oxidative stress. Another severe damage is hypoxemia in patients that do not receive adequate respiratory support. The neurological symptoms that the patient presents, will depend on factors that condition the expression of ACE2 in the brain such as age and sex, as well as the mechanism of neuronal invasion, the immune response and the general state of the patient. Clinical and histopathological studies have described neurological alterations in human patients with COVID-19. These conditions could have a possible contribution to the morbidity and mortality caused by this disease and may even represent the onset of neurodegenerative activity in recovered patients.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Encéfalo/virologia , COVID-19/epidemiologia , Doenças Transmissíveis/virologia , SARS-CoV-2/patogenicidade , COVID-19/virologia , Humanos , Neurônios/virologia
11.
Nat Commun ; 12(1): 2855, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001896

RESUMO

Ebola virus (EBOV) causes neurological symptoms yet its effects on the central nervous system (CNS) are not well-described. Here, we longitudinally assess the acute effects of EBOV on the brain, using quantitative MR-relaxometry, 18F-Fluorodeoxyglucose PET and immunohistochemistry in a monkey model. We report blood-brain barrier disruption, likely related to high cytokine levels and endothelial viral infection, with extravasation of fluid, Gadolinium-based contrast material and albumin into the extracellular space. Increased glucose metabolism is also present compared to the baseline, especially in the deep gray matter and brainstem. This regional hypermetabolism corresponds with mild neuroinflammation, sporadic neuronal infection and apoptosis, as well as increased GLUT3 expression, consistent with increased neuronal metabolic demands. Neuroimaging changes are associated with markers of disease progression including viral load and cytokine/chemokine levels. Our results provide insight into the pathophysiology of CNS involvement with EBOV and may help assess vaccine/treatment efficacy in real time.


Assuntos
Encéfalo/diagnóstico por imagem , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Doença pelo Vírus Ebola/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Encéfalo/metabolismo , Encéfalo/virologia , Citocinas/metabolismo , Ebolavirus/fisiologia , Haplorrinos , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno , Humanos
12.
Front Immunol ; 12: 665300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981312

RESUMO

The irruption of SARS-CoV-2 during 2020 has been of pandemic proportions due to its rapid spread and virulence. COVID-19 patients experience respiratory, digestive and neurological symptoms. Distinctive symptom as anosmia, suggests a potential neurotropism of this virus. Amongst the several pathways of entry to the nervous system, we propose an alternative pathway from the infection of the gut, involving Toll-like receptor 4 (TLR4), zonulin, protease-activated receptor 2 (PAR2) and zonulin brain receptor. Possible use of zonulin antagonists could be investigated to attenuate neurological manifestations caused by SARS-CoV-19 infection.


Assuntos
COVID-19/complicações , Haptoglobinas/metabolismo , Doenças do Sistema Nervoso/complicações , Precursores de Proteínas/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Encéfalo/metabolismo , Encéfalo/virologia , COVID-19/metabolismo , COVID-19/virologia , Proteínas do Sistema Complemento/metabolismo , Gastroenteropatias/complicações , Gastroenteropatias/metabolismo , Gastroenteropatias/virologia , Humanos , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/virologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Receptor 4 Toll-Like/metabolismo
13.
Biofactors ; 47(2): 232-241, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: covidwho-1178977

RESUMO

COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.


Assuntos
COVID-19/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Fadiga/tratamento farmacológico , Luteolina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encéfalo/virologia , COVID-19/complicações , COVID-19/fisiopatologia , COVID-19/virologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/virologia , Citocinas/genética , Fadiga/complicações , Fadiga/fisiopatologia , Fadiga/virologia , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/virologia , SARS-CoV-2/patogenicidade
14.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1134166

RESUMO

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood-brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Barreira Hematoencefálica/virologia , COVID-19/virologia , SARS-CoV-2/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/virologia , COVID-19/epidemiologia , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/virologia , Comorbidade , Humanos , SARS-CoV-2/química , Tropismo Viral
15.
Acta Neuropathol ; 141(6): 809-822, 2021 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1202748

RESUMO

One of the most frequent symptoms of COVID-19 is the loss of smell and taste. Based on the lack of expression of the virus entry proteins in olfactory receptor neurons, it was originally assumed that the new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) does not infect olfactory neurons. Recent studies have reported otherwise, opening the possibility that the virus can directly infect the brain by traveling along the olfactory nerve. Multiple animal models have been employed to assess mechanisms and routes of brain infection of SARS-CoV-2, often with conflicting results. We here review the current evidence for an olfactory route to brain infection and conclude that the case for infection of olfactory neurons is weak, based on animal and human studies. Consistent brain infection after SARS-CoV-2 inoculation in mouse models is only seen when the virus entry proteins are expressed abnormally, and the timeline and progression of rare neuro-invasion in these and in other animal models points to alternative routes to the brain, other than along the olfactory projections. COVID-19 patients can be assured that loss of smell does not necessarily mean that the SARS-CoV-2 virus has gained access to and has infected their brains.


Assuntos
Encéfalo/virologia , COVID-19/etiologia , Nervo Olfatório/virologia , Neurônios Receptores Olfatórios/virologia , SARS-CoV-2/fisiologia , Internalização do Vírus , Animais , Modelos Animais de Doenças , Humanos
16.
Pediatr Infect Dis J ; 40(7): e268-e269, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1201334

RESUMO

Coronavirus disease 2019 (COVID-19) symptoms in newborn infants are incompletely described. We present the first case of neuroradiologic abnormality associated with COVID-19 in a newborn infant with afebrile seizure. This case underlines the possible neurologic involvement of severe acute respiratory syndrome coronavirus 2 in this age group.


Assuntos
COVID-19/complicações , Convulsões/virologia , Substância Branca/patologia , Substância Branca/virologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/virologia , COVID-19/diagnóstico , COVID-19/fisiopatologia , Febre , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Convulsões/etiologia
17.
Pediatr Infect Dis J ; 40(7): e270-e271, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1201291

RESUMO

The majority of coronavirus disease 2019 (COVID-19) have been confirmed in adults, with only a few reported cases in children. In the pediatric population, COVID-19 infection appears to be often unremarkable or associated with mild respiratory symptoms. Little is known about neurologic complications related to COVID-19 in newborns. We present a case of severe encephalitis with cytotoxic brain edema in a newborn with COVID-19.


Assuntos
Edema Encefálico/patologia , Edema Encefálico/virologia , Encéfalo/patologia , COVID-19/complicações , Encefalite Viral/etiologia , Doença Aguda , Encéfalo/diagnóstico por imagem , Encéfalo/virologia , Edema Encefálico/diagnóstico por imagem , COVID-19/diagnóstico , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Imageamento por Ressonância Magnética , Masculino , Gravidez , Complicações Infecciosas na Gravidez/virologia , Convulsões/virologia
18.
Signal Transduct Target Ther ; 6(1): 169, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: covidwho-1199270

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
19.
Biofactors ; 47(2): 232-241, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33847020

RESUMO

COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.


Assuntos
COVID-19/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Fadiga/tratamento farmacológico , Luteolina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encéfalo/virologia , COVID-19/complicações , COVID-19/fisiopatologia , COVID-19/virologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/virologia , Citocinas/genética , Fadiga/complicações , Fadiga/fisiopatologia , Fadiga/virologia , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/virologia , SARS-CoV-2/patogenicidade
20.
Acta Neuropathol ; 141(6): 809-822, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33903954

RESUMO

One of the most frequent symptoms of COVID-19 is the loss of smell and taste. Based on the lack of expression of the virus entry proteins in olfactory receptor neurons, it was originally assumed that the new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) does not infect olfactory neurons. Recent studies have reported otherwise, opening the possibility that the virus can directly infect the brain by traveling along the olfactory nerve. Multiple animal models have been employed to assess mechanisms and routes of brain infection of SARS-CoV-2, often with conflicting results. We here review the current evidence for an olfactory route to brain infection and conclude that the case for infection of olfactory neurons is weak, based on animal and human studies. Consistent brain infection after SARS-CoV-2 inoculation in mouse models is only seen when the virus entry proteins are expressed abnormally, and the timeline and progression of rare neuro-invasion in these and in other animal models points to alternative routes to the brain, other than along the olfactory projections. COVID-19 patients can be assured that loss of smell does not necessarily mean that the SARS-CoV-2 virus has gained access to and has infected their brains.


Assuntos
Encéfalo/virologia , COVID-19/etiologia , Nervo Olfatório/virologia , Neurônios Receptores Olfatórios/virologia , SARS-CoV-2/fisiologia , Internalização do Vírus , Animais , Modelos Animais de Doenças , Humanos
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