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1.
Trop Biomed ; 38(3): 435-445, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34608117

RESUMO

Ever since the first reported case series on SARS-CoV-2-induced neurological manifestation in Wuhan, China in April 2020, various studies reporting similar as well as diverse symptoms of COVID-19 infection relating to the nervous system were published. Since then, scientists started to uncover the mechanism as well as pathophysiological impacts it has on the current understanding of the disease. SARS-CoV-2 binds to the ACE2 receptor which is present in certain parts of the body which are responsible for regulating blood pressure and inflammation in a healthy system. Presence of the receptor in the nasal and oral cavity, brain, and blood allows entry of the virus into the body and cause neurological complications. The peripheral and central nervous system could also be invaded directly in the neurogenic or hematogenous pathways, or indirectly through overstimulation of the immune system by cytokines which may lead to autoimmune diseases. Other neurological implications such as hypoxia, anosmia, dysgeusia, meningitis, encephalitis, and seizures are important symptoms presented clinically in COVID-19 patients with or without the common symptoms of the disease. Further, patients with higher severity of the SARS-CoV-2 infection are also at risk of retaining some neurological complications in the long-run. Treatment of such severe hyperinflammatory conditions will also be discussed, as well as the risks they may pose to the progression of the disease. For this review, articles pertaining information on the neurological manifestation of SARS-CoV-2 infection were gathered from PubMed and Google Scholar using the search keywords "SARS-CoV-2", "COVID-19", and "neurological dysfunction". The findings of the search were filtered, and relevant information were included.


Assuntos
COVID-19/patologia , Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso/virologia , Sistema Nervoso Periférico/patologia , Enzima de Conversão de Angiotensina 2/metabolismo , Anosmia/virologia , Sistema Nervoso Central/virologia , Disgeusia/virologia , Encefalite Viral/virologia , Humanos , Meningite Viral/virologia , Doenças do Sistema Nervoso/patologia , Sistema Nervoso Periférico/virologia , SARS-CoV-2 , Convulsões/virologia
2.
Viruses ; 13(10)2021 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-34696521

RESUMO

Coronavirus 2019 (COVID-19) is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the lungs. COVID-19 symptoms include the presence of fevers, dry coughs, fatigue, sore throat, headaches, diarrhea, and a loss of taste or smell. However, it is understood that SARS-CoV-2 is neurotoxic and neuro-invasive and could enter the central nervous system (CNS) via the hematogenous route or via the peripheral nerve route and causes encephalitis, encephalopathy, and acute disseminated encephalomyelitis (ADEM) in COVID-19 patients. This review discusses the possibility of SARS-CoV-2-mediated Multiple Sclerosis (MS) development in the future, comparable to the surge in Parkinson's disease cases following the Spanish Flu in 1918. Moreover, the SARS-CoV-2 infection is associated with a cytokine storm. This review highlights the impact of these modulated cytokines on glial cell interactions within the CNS and their role in potentially prompting MS development as a secondary disease by SARS-CoV-2. SARS-CoV-2 is neurotropic and could interfere with various functions of neurons leading to MS development. The influence of neuroinflammation, microglia phagocytotic capabilities, as well as hypoxia-mediated mitochondrial dysfunction and neurodegeneration, are mechanisms that may ultimately trigger MS development.


Assuntos
COVID-19/complicações , COVID-19/patologia , Sistema Nervoso Central/patologia , Esclerose Múltipla/patologia , Doenças Neurodegenerativas/virologia , Sistema Nervoso Central/virologia , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Citocinas/metabolismo , História do Século XX , Humanos , Influenza Pandêmica, 1918-1919/estatística & dados numéricos , Esclerose Múltipla/virologia , Doenças Neurodegenerativas/patologia , SARS-CoV-2/imunologia
3.
Nat Commun ; 12(1): 5401, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518549

RESUMO

Fast-replicating neurotropic herpesviruses exemplified by herpes simplex virus-1 (HSV-1) naturally infect the central nervous system (CNS). However, most individuals intrinsically suppress the virus during a primary infection and preclude it from significantly damaging the CNS. Optineurin (OPTN) is a conserved autophagy receptor with little understanding of its role in neurotropic viral infections. We show that OPTN selectively targets HSV-1 tegument protein, VP16, and the fusion glycoprotein, gB, to degradation by autophagy. OPTN-deficient mice challenged with HSV-1 show significant cognitive decline and susceptibility to lethal CNS infection. OPTN deficiency unveils severe consequences for recruitment of adaptive immunity and suppression of neuronal necroptosis. Ocular HSV-1 infection is lethal without OPTN and is rescued using a necroptosis inhibitor. These results place OPTN at the crux of neuronal survival from potentially lethal CNS viral infections.


Assuntos
Proteínas de Ciclo Celular/genética , Sistema Nervoso Central/metabolismo , Herpes Simples/genética , Proteínas de Membrana Transportadoras/genética , Animais , Autofagia/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Sistema Nervoso Central/virologia , Chlorocebus aethiops , Células HeLa , Herpes Simples/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necroptose/genética , Neurônios/metabolismo , Neurônios/virologia , Fármacos Neuroprotetores/metabolismo , Interferência de RNA , Células Vero , Replicação Viral/genética
4.
Viruses ; 13(7)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34372576

RESUMO

Virus-induced infections of the central nervous system (CNS) are among the most serious problems in public health and can be associated with high rates of morbidity and mortality, mainly in low- and middle-income countries, where these manifestations have been neglected. Typically, herpes simplex virus 1 and 2, varicella-zoster, and enterovirus are responsible for a high number of cases in immunocompetent hosts, whereas other herpesviruses (for example, cytomegalovirus) are the most common in immunocompromised individuals. Arboviruses have also been associated with outbreaks with a high burden of neurological disorders, such as the Zika virus epidemic in Brazil. There is a current lack of understanding in Brazil about the most common viruses involved in CNS infections. In this review, we briefly summarize the most recent studies and findings associated with the CNS, in addition to epidemiological data that provide extensive information on the circulation and diversity of the most common neuro-invasive viruses in Brazil. We also highlight important aspects of the prion-associated diseases. This review provides readers with better knowledge of virus-associated CNS infections. A deeper understanding of these infections will support the improvement of the current surveillance strategies to allow the timely monitoring of the emergence/re-emergence of neurotropic viruses.


Assuntos
Doenças do Sistema Nervoso Central/virologia , Infecções do Sistema Nervoso Central/epidemiologia , Doenças Priônicas/epidemiologia , Alphavirus/patogenicidade , Brasil/epidemiologia , Sistema Nervoso Central/virologia , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/fisiopatologia , Infecções do Sistema Nervoso Central/virologia , Viroses do Sistema Nervoso Central/fisiopatologia , Viroses do Sistema Nervoso Central/virologia , Enterovirus/patogenicidade , Flavivirus/patogenicidade , Herpesviridae/patogenicidade , Humanos , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/virologia , Doenças Priônicas/fisiopatologia , Príons/metabolismo , Príons/patogenicidade , Simplexvirus/patogenicidade , Viroses/virologia , Vírus/patogenicidade , Zika virus/patogenicidade
5.
Brain Pathol ; 31(6): e13013, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34390282

RESUMO

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the new coronavirus responsible for the pandemic disease in the last year, is able to affect the central nervous system (CNS). Compared with its well-known pulmonary tropism and respiratory complications, little has been studied about SARS-CoV-2 neurotropism and pathogenesis of its neurological manifestations, but also about postmortem histopathological findings in the CNS of patients who died from COVID-19 (coronavirus disease 2019). We present a systematic review, carried out according to the Preferred Reporting Items for Systematic Review standards, of the neuropathological features of COVID-19. We found 21 scientific papers, the majority of which refer to postmortem examinations; the total amount of cases is 197. Hypoxic changes are the most frequently reported alteration of brain tissue, followed by ischemic and hemorrhagic lesions and reactive astrogliosis and microgliosis. These findings do not seem to be specific to SARS-CoV-2 infection, they are more likely because of systemic inflammation and coagulopathy caused by COVID-19. More studies are needed to confirm this hypothesis and to detect other possible alterations of neural tissue. Brain examination of patients dead from COVID-19 should be included in a protocol of standardized criteria to perform autopsies on these subjects.


Assuntos
Encéfalo/fisiologia , Encéfalo/virologia , COVID-19/patologia , Doenças do Sistema Nervoso/virologia , SARS-CoV-2/metabolismo , Encéfalo/fisiopatologia , COVID-19/metabolismo , COVID-19/virologia , Sistema Nervoso Central/fisiologia , Sistema Nervoso Central/virologia , Humanos , Inflamação/patologia , Inflamação/virologia , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/patologia , Pandemias
6.
PLoS One ; 16(7): e0254872, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34280238

RESUMO

BACKGROUND: COVID-19 is only partly understood, and the level of evidence available in terms of pathophysiology, epidemiology, therapy, and long-term outcome remains limited. During the early phase of the pandemic, it was necessary to effectively investigate all aspects of this new disease. Autopsy can be a valuable procedure to investigate the internal organs with special techniques to obtain information on the disease, especially the distribution and type of organ involvement. METHODS: During the first wave of COVID-19 in Germany, autopsies of 19 deceased patients were performed. Besides gross examination, the organs were analyzed with standard histology and polymerase-chain-reaction for SARS-CoV-2. Polymerase chain reaction positive localizations were further analyzed with immunohistochemistry and RNA-in situ hybridization for SARS-CoV-2. RESULTS: Eighteen of 19 patients were found to have died due to COVID-19. Clinically relevant histological changes were only observed in the lungs. Diffuse alveolar damage in considerably different degrees was noted in 18 cases. Other organs, including the central nervous system, did not show specific micromorphological alterations. In terms of SARS-CoV-2 detection, the focus remains on the upper airways and lungs. This is true for both the number of positive samples and the viral load. A highly significant inverse correlation between the stage of diffuse alveolar damage and viral load was found on a case and a sample basis. Mediastinal lymph nodes and fat were also affected by the virus at high frequencies. By contrast, other organs rarely exhibited a viral infection. Moderate to strong correlations between the methods for detecting SARS-CoV-2 were observed for the lungs and for other organs. CONCLUSIONS: The lung is the most affected organ in gross examination, histology and polymerase chain reaction. SARS-CoV-2 detection in other organs did not reveal relevant or specific histological changes. Moreover, we did not find CNS involvement.


Assuntos
COVID-19/virologia , Sistema Nervoso Central/virologia , Pulmão/virologia , Linfonodos/virologia , Carga Viral , Idoso , Idoso de 80 Anos ou mais , Autopsia/estatística & dados numéricos , COVID-19/epidemiologia , COVID-19/patologia , Sistema Nervoso Central/patologia , Feminino , Humanos , Pulmão/patologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade
7.
J Chem Neuroanat ; 117: 102006, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34324964

RESUMO

Nowadays, Covid-19 is considered a serious health problem worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has sparked a global pandemic of the coronavirus disease of 2019 (COVID-19). It is well known that the Corona Virus attacks mainly the respiratory system. Meanwhile, it has been established that coronavirus infection can extend beyond the respiratory system and unfortunately, can also affect our nervous system. Multiple neurological symptoms and signs had been documented during and post covid conditions. This virus gets access to the central nervous system (CNS) via the bloodstream leading to infect the endothelial lining cells. Also, it was reported that the virus can enter the peripheral nervous system via retrograde neuronal routes. The virus could be internalized in nerve synapses through endocytosis, transported retrogradely, and spread trans-synoptically to other brain regions. This minireview highlights the possible routes by which SARS-CoV-2 can invade the central nervous system (CNS) and its pathophysiology and manifestation.


Assuntos
Encéfalo/fisiopatologia , COVID-19/fisiopatologia , Viroses do Sistema Nervoso Central/fisiopatologia , SARS-CoV-2/fisiologia , Animais , Encéfalo/virologia , COVID-19/complicações , COVID-19/epidemiologia , Sistema Nervoso Central/fisiopatologia , Sistema Nervoso Central/virologia , Viroses do Sistema Nervoso Central/etiologia , Humanos , SARS-CoV-2/isolamento & purificação
8.
Viruses ; 13(5)2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066091

RESUMO

Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD, some hypotheses have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients, in general, and for the PD cases reported, in particular. Given the importance of this potential connection, we present here a molecular-level mechanistic hypothesis that explains well these findings and will serve to explore the potential CNS damage in COVID-19 patients. The model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Our hypothesis is supported by finding 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. The molecular-level mechanistic hypothesis presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.


Assuntos
COVID-19/complicações , Doença de Parkinson Secundária/etiologia , COVID-19/metabolismo , Sistema Nervoso Central/virologia , Exossomos/metabolismo , Humanos , Pulmão/metabolismo , Modelos Teóricos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/virologia , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/virologia , Mapas de Interação de Proteínas , SARS-CoV-2/patogenicidade , Proteínas Virais/metabolismo
9.
Neurotox Res ; 39(5): 1613-1629, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34169404

RESUMO

Aside from the respiratory distress as the predominant clinical presentation of SARS-CoV-2 infection, various neurological complications have been reported with the infection during the ongoing pandemic, some of which cause serious morbidity and mortality. Herein, we gather the latest anatomical evidence of the virus's presence within the central nervous system. We then delve into the possible SARS-CoV-2 entry routes into the neurological tissues, with the hematogenous and the neuronal routes as the two utmost passage routes into the nervous system. We then give a comprehensive review of the neurological manifestations of the SARS-CoV-2 invasion in both the central and peripheral nervous system and its underlying pathophysiology via investigating large studies in the field and case reports in cases of study scarcity.


Assuntos
COVID-19/complicações , COVID-19/fisiopatologia , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/fisiopatologia , COVID-19/virologia , Sistema Nervoso Central/virologia , Humanos , Doenças do Sistema Nervoso/virologia , Sistema Nervoso Periférico/virologia
10.
J Virol ; 95(16): e0057321, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34076486

RESUMO

The 2015/2016 Zika virus epidemic in South and Central America left the scientific community urgently trying to understand the factors that contribute to Zika virus pathogenesis. Because multiple other flaviviruses are endemic in areas where Zika virus emerged, it is hypothesized that a key to understanding Zika virus disease severity is to study Zika virus infection in the context of prior flavivirus exposure. Human and animal studies have highlighted the idea that having been previously exposed to a different flavivirus may modulate the immune response to Zika virus. However, it is still unclear how prior flavivirus exposure impacts Zika viral burden and disease. In this murine study, we longitudinally examine multiple factors involved in Zika disease, linking viral burden with increased neurological disease severity, weight loss, and inflammation. We show that prior heterologous flavivirus exposure with dengue virus type 2 or 3 or the vaccine strain of yellow fever provides protection from mortality in a lethal Zika virus challenge. However, reduction in viral burden and Zika disease varies depending on the infecting primary flavivirus; with primary Zika virus infection being most protective from Zika virus challenge, followed by dengue virus 2, with yellow fever and dengue virus 3 protecting against mortality but showing more severe disease. This study demonstrates the variation in protective effects of prior flavivirus exposure on Zika virus pathogenesis and identifies distinct relationships between primary flavivirus infection and the potential for Zika virus disease. IMPORTANCE The emergence and reemergence of various vector-borne diseases in recent years highlights the need to understand the mechanisms of protection for each pathogen. In this study, we investigated the impact of prior exposure to Zika virus, dengue virus serotypes 2 or 3, or the vaccine strain of yellow fever on pathogenesis and disease outcomes in a mouse model of Zika virus infection. We found that prior exposure to a heterologous flavivirus was protective from mortality, and to varying degrees, prior flavivirus exposure was protective against neurological disease, weight loss, and severe viral burden during a lethal Zika challenge. Using a longitudinal and cross-sectional study design, we were able to link multiple disease parameters, including viral burden, with neurological disease severity, weight loss, and inflammatory response in the context of flavivirus infection. This study demonstrates a measurable but varied impact of prior flavivirus exposure in modulating flavivirus pathophysiology. Given the cyclic nature of most flavivirus outbreaks, this work will contribute to the forecasting of disease severity for future outbreaks.


Assuntos
Flavivirus/imunologia , Imunidade Heteróloga , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/virologia , Proteção Cruzada , Citocinas/metabolismo , Vírus da Dengue/imunologia , Modelos Animais de Doenças , Progressão da Doença , Inflamação , Camundongos , Carga Viral , Viremia/imunologia , Vírus da Febre Amarela/imunologia , Zika virus/patogenicidade , Infecção por Zika virus/mortalidade , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
11.
Mol Neurobiol ; 58(9): 4575-4587, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34110602

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 or COVID-19 has been declared as a pandemic disease by the World Health Organization (WHO). Globally, this disease affected 159 million of the population and reported ~ 3.3 million deaths to the current date (May 2021). There is no definitive treatment strategy that has been identified, although this disease has prevailed in its current form for the past 18 months. The main challenges in the (SARS-CoV)-2 infections are in identifying the heterogeneity in viral strains and the plausible mechanisms of viral infection to human tissues. In parallel to the investigations into the patho-mechanism of SARS-CoV-2 infection, understanding the fundamental processes underlying the clinical manifestations of COVID-19 is very crucial for designing effective therapies. Since neurological symptoms are very apparent in COVID-19 infected patients, here, we tried to emphasize the involvement of redox imbalance and subsequent mitochondrial dysfunction in the progression of the COVID-19 infection. It has been articulated that mitochondrial dysfunction is very apparent and also interlinked to neurological symptoms in COVID-19 infection. Overall, this article provides an in-depth overview of redox imbalance and mitochondrial dysfunction involvement in aggravating COVID-19 infection and its probable contribution to the neurological manifestation of the disease.


Assuntos
COVID-19/complicações , Mitocôndrias/fisiologia , SARS-CoV-2/patogenicidade , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/metabolismo , Sistema Nervoso Central/virologia , Reposicionamento de Medicamentos , Endotélio Vascular/fisiopatologia , Endotélio Vascular/virologia , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Modelos Biológicos , Nervo Olfatório/virologia , Especificidade de Órgãos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Pandemias , SARS-CoV-2/fisiologia , Proteínas Virais/fisiologia , Tropismo Viral , Viremia/complicações , Virulência , Internalização do Vírus
12.
Mol Neurobiol ; 58(9): 4694-4715, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34169443

RESUMO

The unremitting coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marked a year-long phase of public health adversaries and has severely compromised healthcare globally. Early evidence of COVID-19 noted its impact on the pulmonary and cardiovascular functions, while multiple studies in recent time shed light on its substantial neurological complications, though a comprehensive understanding of the cause(s), the mechanism(s), and their neuropathological outcomes is scarce. In the present review, we conferred evidence of neurological complications in COVID-19 patients and shed light on the SARS-CoV-2 infection routes including the hematogenous, direct/neuronal, lymphatic tissue or cerebrospinal fluid, or infiltration through infected immune cells, while the underlying mechanism of SARS-CoV-2 invasion to the central nervous system (CNS) was also discussed. In an up-to-date manner, we further reviewed the impact of COVID-19 in developing diverse neurologic manifestations associated with CNS, peripheral nervous system (PNS), skeletal muscle, and also pre-existing neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and myasthenia gravis. Furthermore, we discussed the involvement of key factors including age, sex, comorbidity, and disease severity in exacerbating the neurologic manifestations in COVID-19 patients. An outlook of present therapeutic strategies and state of existing challenges in COVID-19 management was also accessed. Conclusively, the present report provides a comprehensive review of COVID-19-related neurological complications and emphasizes the need for their early clinical management in the ongoing COVID-19 pandemic.


Assuntos
COVID-19/complicações , Doenças do Sistema Nervoso/etiologia , Pandemias , SARS-CoV-2/patogenicidade , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes do Sistema Nervoso/epidemiologia , Doenças Autoimunes do Sistema Nervoso/etiologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Sistema Nervoso Central/virologia , Criança , Comorbidade , Feminino , Humanos , Sistema Imunitário/virologia , Inflamação , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Doenças Musculares/etiologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/fisiopatologia , Doenças Neurodegenerativas/complicações , Neurônios/virologia , Especificidade de Órgãos , Fatores Sexuais , Viremia/induzido quimicamente , Viremia/imunologia , Internalização do Vírus
13.
Front Immunol ; 12: 656700, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936086

RESUMO

SARS-CoV-2, the novel coronavirus infection has consistently shown an association with neurological anomalies in patients, in addition to its usual respiratory distress syndrome. Multi-organ dysfunctions including neurological sequelae during COVID-19 persist even after declining viral load. We propose that SARS-CoV-2 gene product, Spike, is able to modify the host exosomal cargo, which gets transported to distant uninfected tissues and organs and can initiate a catastrophic immune cascade within Central Nervous System (CNS). SARS-CoV-2 Spike transfected cells release a significant amount of exosomes loaded with microRNAs such as miR-148a and miR-590. microRNAs gets internalized by human microglia and suppress target gene expression of USP33 (Ubiquitin Specific peptidase 33) and downstream IRF9 levels. Cellular levels of USP33 regulate the turnover time of IRF9 via deubiquitylation. Our results also demonstrate that absorption of modified exosomes effectively regulate the major pro-inflammatory gene expression profile of TNFα, NF-κB and IFN-ß. These results uncover a bystander pathway of SARS-CoV-2 mediated CNS damage through hyperactivation of human microglia. Our results also attempt to explain the extra-pulmonary dysfunctions observed in COVID-19 cases when active replication of virus is not supported. Since Spike gene and mRNAs have been extensively picked up for vaccine development; the knowledge of host immune response against spike gene and protein holds a great significance. Our study therefore provides novel and relevant insights regarding the impact of Spike gene on shuttling of host microRNAs via exosomes to trigger the neuroinflammation.


Assuntos
COVID-19/metabolismo , Exossomos/metabolismo , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/metabolismo , MicroRNAs/metabolismo , Microglia/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Ubiquitina Tiolesterase/metabolismo , COVID-19/genética , COVID-19/fisiopatologia , COVID-19/virologia , Linhagem Celular , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/fisiopatologia , Sistema Nervoso Central/virologia , Endopeptidases/metabolismo , Exossomos/genética , Exossomos/patologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Interferon beta/metabolismo , MicroRNAs/genética , Microglia/patologia , NF-kappa B/metabolismo , Estabilidade Proteica , Fator de Necrose Tumoral alfa/metabolismo
14.
PLoS One ; 16(4): e0250708, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33909679

RESUMO

BACKGROUND: Coronavirus disease (COVID-19) is the pandemic caused by SARS-CoV-2 that has caused more than 2.2 million deaths worldwide. We summarize the reported pathologic findings on biopsy and autopsy in patients with severe/fatal COVID-19 and documented the presence and/or effect of SARS-CoV-2 in all organs. METHODS AND FINDINGS: A systematic search of the PubMed, Embase, MedRxiv, Lilacs and Epistemonikos databases from January to August 2020 for all case reports and case series that reported histopathologic findings of COVID-19 infection at autopsy or tissue biopsy was performed. 603 COVID-19 cases from 75 of 451 screened studies met inclusion criteria. The most common pathologic findings were lungs: diffuse alveolar damage (DAD) (92%) and superimposed acute bronchopneumonia (27%); liver: hepatitis (21%), heart: myocarditis (11.4%). Vasculitis was common only in skin biopsies (25%). Microthrombi were described in the placenta (57.9%), lung (38%), kidney (20%), Central Nervous System (CNS) (18%), and gastrointestinal (GI) tract (2%). Injury of endothelial cells was common in the lung (18%) and heart (4%). Hemodynamic changes such as necrosis due to hypoxia/hypoperfusion, edema and congestion were common in kidney (53%), liver (48%), CNS (31%) and GI tract (18%). SARS-CoV-2 viral particles were demonstrated within organ-specific cells in the trachea, lung, liver, large intestine, kidney, CNS either by electron microscopy, immunofluorescence, or immunohistochemistry. Additional tissues were positive by Polymerase Chain Reaction (PCR) tests only. The included studies were from numerous countries, some were not peer reviewed, and some studies were performed by subspecialists, resulting in variable and inconsistent reporting or over statement of the reported findings. CONCLUSIONS: The main pathologic findings of severe/fatal COVID-19 infection are DAD, changes related to coagulopathy and/or hemodynamic compromise. In addition, according to the observed organ damage myocarditis may be associated with sequelae.


Assuntos
COVID-19/metabolismo , COVID-19/fisiopatologia , Autopsia/métodos , Biópsia/métodos , Sistema Nervoso Central/virologia , Células Endoteliais/virologia , Feminino , Trato Gastrointestinal/virologia , Coração/virologia , Humanos , Rim/virologia , Fígado/virologia , Pulmão/virologia , Pandemias/estatística & dados numéricos , Placenta/virologia , Gravidez , SARS-CoV-2/patogenicidade , Coloração e Rotulagem/métodos , Traqueia/virologia
15.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920904

RESUMO

COVID-19 is a severe respiratory disease caused by the newly identified human coronavirus (HCoV) Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The virus was discovered in December 2019, and in March 2020, the disease was declared a global pandemic by the World Health Organization (WHO) due to a high number of cases. Although SARS-CoV-2 primarily affects the respiratory system, several studies have reported neurological complications in COVID-19 patients. Headache, dizziness, loss of taste and smell, encephalitis, encephalopathy, and cerebrovascular diseases are the most common neurological complications that are associated with COVID-19. In addition, seizures, neuromuscular junctions' disorders, and Guillain-Barré syndrome were reported as complications of COVID-19, as well as neurodegenerative and demyelinating disorders. However, the management of these conditions remains a challenge. In this review, we discuss the prevalence, pathogenesis, and mechanisms of these neurological sequelae that are secondary to SARS-CoV-2 infection. We aim to update neurologists and healthcare workers on the possible neurological complications associated with COVID-19 and the management of these disease conditions.


Assuntos
COVID-19/complicações , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/virologia , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/virologia , Humanos , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/virologia , Prevalência , SARS-CoV-2/metabolismo
16.
Medicine (Baltimore) ; 100(17): e25716, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907160

RESUMO

ABSTRACT: Although influenza is generally an acute, self-limited, and uncomplicated disease in healthy children, it can result in severe morbidity and mortality. The objectives of this study were to analyze and compare the clinical features and outcome of severe pediatric influenza with and without central nervous system (CNS) involvement.We conducted a retrospective observational study of children admitted to the pediatric intensive care unit (PICU) of China Medical University Children's Hospital in Taiwan with a confirmed diagnosis of influenza. The demographic data, clinical and laboratory presentations, therapeutic strategies, and neurodevelopmental outcomes for these patients were analyzed. Furthermore, comparison of patients with and without CNS involvement was conducted.A total of 32 children with severe influenza were admitted during the study periods. Sixteen children were categorized as the non-CNS (nCNS) group and 16 children were categorized as the CNS group. Nine of them had underlying disease. The most common complication in the nCNS group was acute respiratory distress syndrome, (n = 8/16), followed by pneumonia (n = 7/16, 44%). In the CNS group, the most lethal complication was acute necrotizing encephalopathy (n = 3/16) which led to 3 deaths. The overall mortality rate was higher in the CNS group (n = 6) than in the nCNS group (n = 1) (37.5% vs 6.25%, P = .03).The mortality rate of severe complicated influenza was significantly higher with CNS involvement. Children with primary cardiopulmonary abnormalities were at high risk of developing severe complicated influenza, while previously healthy children exhibited risk for influenza-associated encephalitis/encephalopathy.


Assuntos
Encefalite Viral , Influenza Humana , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Transtornos do Neurodesenvolvimento , Sistema Nervoso Central/virologia , Criança , Encefalite Viral/diagnóstico , Encefalite Viral/etiologia , Encefalite Viral/mortalidade , Feminino , Humanos , Vírus da Influenza A/isolamento & purificação , Influenza Humana/epidemiologia , Influenza Humana/fisiopatologia , Influenza Humana/terapia , Influenza Humana/virologia , Masculino , Mortalidade , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Avaliação de Processos e Resultados em Cuidados de Saúde , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Taiwan/epidemiologia
17.
Emerg Microbes Infect ; 10(1): 913-928, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33905300

RESUMO

Rabies remains a public health threat in most parts of the world. Dogs, especially stray dogs, are the main sources of rabies transmission in developing countries, while wild animals are primarily responsible for the spread of rabies in developed countries and play an emerging role in rabies transmission in developing countries. Oral vaccination is the most practical method for rabies control in these animals, and the greatest challenge for oral vaccination is the hostile environment and large quantity of proteases in the gastrointestinal tract. In the present study, a promising adjuvant with potential protease inhibitory activity, unlipidated outer membrane protein 19 (U-OMP19), was inserted into the genome of the recombinant rabies virus (rRABV) strain LBNSE, designated LBNSE-U-OMP19, and the immunogenicity of LBNSE-U-OMP19 was investigated. LBNSE-U-OMP19 could potentially protect viral glycoprotein from digestion by gastrointestinal fluids in vitro. The expression of U-OMP19 attenuated viral pathogenicity by restricting viral replication in the central nervous system (CNS) and repressing the production of inflammatory chemokines and cytokines. After oral vaccination, LBNSE-U-OMP19 recruited dendritic cells (DCs), follicular helper T (TFH) cells and germinal center (GC) B cells, promoted the formation of GCs, and increased the population of plasma cells in immunized mice, resulting in higher levels of RABV-neutralizing antibodies and better protection in mice immunized with LBNSE-U-OMP19 than in those immunized with the parent virus LBNSE. Together, our data suggest that LBNSE-U-OMP19 is a promising candidate for oral rabies vaccines.


Assuntos
Proteínas da Membrana Bacteriana Externa/genética , Células Dendríticas/metabolismo , Centro Germinativo/metabolismo , Vacinas Antirrábicas/administração & dosagem , Vírus da Raiva/fisiologia , Administração Oral , Animais , Anticorpos Neutralizantes/sangue , Proteínas da Membrana Bacteriana Externa/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/virologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunização , Camundongos , Vacinas Antirrábicas/imunologia , Vírus da Raiva/genética , Vírus da Raiva/imunologia , Proteínas Recombinantes/metabolismo , Replicação Viral
18.
Viruses ; 13(3)2021 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673521

RESUMO

Since the 1970s, eight closely related serotypes of classical human astroviruses (HAstV) have been associated with gastrointestinal illness worldwide. In the late 2000s, three genetically unique human astrovirus clades, VA1-VA3, VA2-VA4, and MLB, were described. While the exact disease associated with these clades remains to be defined, VA1 has been associated with central nervous system infections. The discovery that VA1 could be grown in cell culture, supports exciting new studies aimed at understanding viral pathogenesis. Given the association of VA1 with often lethal CNS infections, we tested its susceptibility to the antimicrobial drug, nitazoxanide (NTZ), which we showed could inhibit classical HAstV infections. Our studies demonstrate that NTZ inhibited VA1 replication in Caco2 cells even when added at 12 h post-infection, which is later than in HAstV-1 infection. These data led us to further probe VA1 replication kinetics and cellular responses to infection in Caco-2 cells in comparison to the well-studied HAstV-1 strain. Overall, our studies highlight that VA1 replicates more slowly than HAstV-1 and elicits significantly different cellular responses, including the inability to disrupt cellular junctions and barrier permeability.


Assuntos
Astroviridae/genética , Anti-Infecciosos/farmacologia , Astroviridae/efeitos dos fármacos , Infecções por Astroviridae/tratamento farmacológico , Infecções por Astroviridae/virologia , Células CACO-2 , Linhagem Celular Tumoral , Sistema Nervoso Central/virologia , Humanos , Nitrocompostos/farmacologia , Filogenia , RNA Viral/genética , Tiazóis/farmacologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
19.
mBio ; 12(2)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727362

RESUMO

The human immunodeficiency virus (HIV) enters the central nervous system (CNS) within a few days after primary infection, establishing viral reservoirs that persist even with combined antiretroviral therapy (cART). We show that monocytes from people living with HIV (PLWH) on suppressive cART harboring integrated HIV, viral mRNA, and/or viral proteins preferentially transmigrate across the blood-brain barrier (BBB) to CCL2 and are significantly enriched post-transmigration, and even more highly enriched posttransmigration than T cells with similar properties. Using HIV-infected ART-treated mature monocytes cultured in vitro, we recapitulate these findings and demonstrate that HIV+ CD14+ CD16+ ART-treated monocytes also preferentially transmigrate. Cenicriviroc and anti-JAM-A and anti-ALCAM antibodies significantly and preferentially reduce/block transmigration of HIV+ CD14+ CD16+ ART-treated monocytes. These findings highlight the importance of monocytes in CNS HIV reservoirs and suggest targets to eliminate their formation and reseeding.IMPORTANCE We characterized mechanisms of CNS viral reservoir establishment/replenishment using peripheral blood mononuclear cells (PBMC) of PLWH on cART and propose therapeutic targets to reduce/block selective entry of cells harboring HIV (HIV+) into the CNS. Using DNA/RNAscope, we show that CD14+ CD16+ monocytes with integrated HIV, transcriptionally active, and/or with active viral replication from PBMC of PLWH prescribed cART and virally suppressed, selectively transmigrate across a human BBB model. This is the first study to our knowledge demonstrating that monocytes from PLWH with HIV disease for approximately 22 years and with long-term documented suppression can still carry virus into the CNS that has potential to be reactivated and infectious. This selective entry into the CNS-and likely other tissues-indicates a mechanism of reservoir formation/reseeding in the cART era. Using blocking studies, we propose CCR2, JAM-A, and ALCAM as targets on HIV+ CD14+ CD16+ monocytes to reduce and/or prevent CNS reservoir replenishment and to treat HAND and other HIV-associated comorbidities.


Assuntos
Sistema Nervoso Central/virologia , Reservatórios de Doenças/virologia , Leucócitos Mononucleares/fisiologia , Leucócitos Mononucleares/virologia , Migração Transendotelial e Transepitelial/imunologia , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/virologia , Ensaios de Migração de Leucócitos , Sistema Nervoso Central/efeitos dos fármacos , Quimiocina CCL2/imunologia , Quimiocina CCL2/farmacologia , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Feminino , Infecções por HIV/virologia , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Tioguanina/uso terapêutico
20.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652988

RESUMO

In this Review, we briefly describe the basic virology and pathogenesis of SARS-CoV-2, highlighting how stem cell technology and organoids can contribute to the understanding of SARS-CoV-2 cell tropisms and the mechanism of disease in the human host, supporting and clarifying findings from clinical studies in infected individuals. We summarize here the results of studies, which used these technologies to investigate SARS-CoV-2 pathogenesis in different organs. Studies with in vitro models of lung epithelia showed that alveolar epithelial type II cells, but not differentiated lung alveolar epithelial type I cells, are key targets of SARS-CoV-2, which triggers cell apoptosis and inflammation, while impairing surfactant production. Experiments with human small intestinal organoids and colonic organoids showed that the gastrointestinal tract is another relevant target for SARS-CoV-2. The virus can infect and replicate in enterocytes and cholangiocytes, inducing cell damage and inflammation. Direct viral damage was also demonstrated in in vitro models of human cardiomyocytes and choroid plexus epithelial cells. At variance, endothelial cells and neurons are poorly susceptible to viral infection, thus supporting the hypothesis that neurological symptoms and vascular damage result from the indirect effects of systemic inflammatory and immunological hyper-responses to SARS-CoV-2 infection.


Assuntos
COVID-19/patologia , Organoides/virologia , SARS-CoV-2/fisiologia , Células-Tronco/virologia , Animais , Apoptose , COVID-19/virologia , Sistema Cardiovascular/citologia , Sistema Cardiovascular/patologia , Sistema Cardiovascular/virologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Trato Gastrointestinal/citologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Humanos , Inflamação/patologia , Inflamação/virologia , Pulmão/citologia , Pulmão/patologia , Pulmão/virologia , Organoides/patologia , Células-Tronco/patologia , Tropismo Viral , Internalização do Vírus
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