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1.
Viruses ; 13(10)2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34696502

RESUMO

Herpes simplex virus 1 (HSV-1) and 2 (HSV-2) can infect the central nervous system (CNS) with dire consequences; in children and adults, HSV-1 may cause focal encephalitis, while HSV-2 causes meningitis. In neonates, both viruses can cause severe, disseminated CNS infections with high mortality rates. Here, we differentiated human induced pluripotent stem cells (iPSCs) towards cortical neurons for infection with clinical CNS strains of HSV-1 or HSV-2. Progenies from both viruses were produced at equal quantities in iPSCs, neuroprogenitors and cortical neurons. HSV-1 and HSV-2 decreased viability of neuroprogenitors by 36.0% and 57.6% (p < 0.0001), respectively, 48 h post-infection, while cortical neurons were resilient to infection by both viruses. However, in these functional neurons, both HSV-1 and HSV-2 decreased gene expression of two markers of synaptic activity, CAMK2B and ARC, and affected synaptic activity negatively in multielectrode array experiments. However, unaltered secretion levels of the neurodegeneration markers tau and NfL suggested intact axonal integrity. Viral replication of both viruses was found after six days, coinciding with 6-fold and 22-fold increase in gene expression of cellular RNA polymerase II by HSV-1 and HSV-2, respectively. Our results suggest a resilience of human cortical neurons relative to the replication of HSV-1 and HSV-2.


Assuntos
Diferenciação Celular , Herpes Simples/virologia , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Neurônios/virologia , Diferenciação Celular/genética , Sobrevivência Celular , Sistema Nervoso Central , Regulação da Expressão Gênica , Herpes Simples/patologia , Humanos , Células-Tronco Pluripotentes Induzidas , Neurônios/patologia , Replicação Viral/fisiologia
2.
J Neuroimmunol ; 295-296: 130-8, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27235358

RESUMO

Herpes simplex encephalitis (HSE) is characterized by a pronounced inflammatory activity in the central nervous system (CNS). Here, we investigated the acute and prolonged complement system activity in HSE patients, by using enzyme-linked immunosorbent assays (ELISAs) for numerous complement components (C). We found increased cerebrospinal fluid concentrations of C3a, C3b, C5 and C5a in HSE patients compared with healthy controls. C3a and C5a concentrations remained increased also compared with patient controls. Our results conclude that the complement system is activated in CNS during HSE in the acute phase, and interestingly also in later stages supporting previous reports of prolonged inflammation.


Assuntos
Sistema Nervoso Central/metabolismo , Ativação do Complemento/fisiologia , Proteínas do Sistema Complemento/líquido cefalorraquidiano , Encefalite por Herpes Simples/líquido cefalorraquidiano , Encefalite por Herpes Simples/patologia , Adulto , Idoso , Sistema Nervoso Central/patologia , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Encefalite por Herpes Simples/imunologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
3.
J Neurovirol ; 21(2): 129-47, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25604497

RESUMO

Herpes simplex encephalitis (HSE), targeting the limbic system, is the most common cause of viral encephalitis in the Western world. Two pathways for viral entry to the central nervous system (CNS) in HSE have been suggested: either via the trigeminal nerve or via the olfactory tract. This question remains unsettled, and studies of viral spread between the two brain hemispheres are scarce. Here, we investigated the olfactory infection as a model of infection and tropism of herpes simplex virus 1 (HSV-1), the causative agent of HSE, in the CNS of rats. Rats were instilled with HSV-1 in the right nostril and sacrificed 1-6 days post-infection, and tissues were analysed for viral spread using immunohistochemistry and quantitative PCR (qPCR). After nasal instillation, HSV-1 infected mitral cells of the olfactory bulb (OB) on the right side only, followed by limbic encephalitis. As a novel finding, the anterior commissure (AC) conveyed a rapid transmission of virus between the right and the left OB, acting as a shortcut also between the olfactory cortices. The neuronal cell population that conveyed the viral infection via the AC was positive for the water channel protein aquaporin 9 (AQP9) by immunohistochemistry. Quantification of AQP9 in cerebrospinal fluid samples of HSE patients showed increment as compared to controls. We conclude that the olfactory route and the AC are important for the spread of HSV-1 within the olfactory/limbic system of rats and furthermore, we suggest that AQP9 is involved in viral tropism and pathogenesis of HSE.


Assuntos
Comissura Anterior/virologia , Aquaporinas/metabolismo , Encefalite por Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Mucosa Olfatória/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Comissura Anterior/metabolismo , Modelos Animais de Doenças , Encefalite por Herpes Simples/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/virologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
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