Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice
Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice
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DOI：
10.1371/journal.ppat.1007617
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发表时间：
2019-03-01
期刊：
影响因子：
6.7
通讯作者：
Palamara, Anna Teresa
中科院分区：
文献类型：
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作者：
De Chiara, Giovanna;Piacentini, Roberto;Palamara, Anna Teresa
单纯疱疹病毒1型(HSV-1)是一种DNA嗜神经性病毒，通常在三叉神经节建立潜伏感染，然后周期性地重新激活。尽管许多发现表明HSV-1与阿尔茨海默病(AD)之间存在潜在联系，但因果关系尚未得到证实。因此，我们建立了一种反复反复激活病毒的小鼠HSV-1感染模型。通过病毒学和分子分析，我们发现：1)热应激诱导病毒激活后，HSV-1在不同脑区的扩散和复制；2)AD标志物的积聚，包括淀粉样蛋白、tau过度磷酸化和神经炎症标记物(星形胶质细胞增生、IL-1和IL-6)。值得注意的是，由反复病毒重新激活引发的AD分子生物标记物在HSV-1感染小鼠的大脑皮层和海马区的进行性积累，与认知障碍的增加相关，在七次重新激活后变得不可逆转。综上所述，我们的发现提供了证据，证明在中枢神经系统中轻度和反复的HSV-1感染会产生类似AD的表型，并表明它们是AD的危险因素。作者摘要本文提供了新的证据，即小鼠中的单纯疱疹病毒1型感染在一生中经历反复的病毒重新激活，就像那些反复感染的人类所发生的那样，触发神经退化和认知能力下降的分子标志物的进行性积累，这使人联想到阿尔茨海默病的表型。
Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer's disease (AD), a causal relation has not been demonstrated yet. Hence, we set up a model of recurrent HSV-1 infection in mice undergoing repeated cycles of viral reactivation. By virological and molecular analyses we found: i) HSV-1 spreading and replication in different brain regions after thermal stress-induced virus reactivations; ii) accumulation of AD hallmarks including amyloid- protein, tau hyperphosphorylation, and neuroinflammation markers (astrogliosis, IL-1 and IL-6). Remarkably, the progressive accumulation of AD molecular biomarkers in neocortex and hippocampus of HSV-1 infected mice, triggered by repeated virus reactivations, correlated with increasing cognitive deficits becoming irreversible after seven cycles of reactivation. Collectively, our findings provide evidence that mild and recurrent HSV-1 infections in the central nervous system produce an AD-like phenotype and suggest that they are a risk factor for AD.Author summary This paper provides novel evidence that herpes simplex virus type-1 infection in mice, undergoing repeated virus reactivations throughout life, as occurs in those humans suffering of recurrent infection, triggers progressive accumulation of molecular markers of neurodegeneration and cognitive decline that are reminiscent of Alzheimer's disease phenotype.