Sigmovir Biosystems, Inc., Rockville, Maryland, USA
Sigmovir Biosystems, Inc., Rockville, Maryland, USA.
J Virol. 2019 Dec 12;94(1). doi: 10.1128/JVI.01161-19.
Demyelinating central nervous system (CNS) disorders like multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) have been difficult to study and treat due to the lack of understanding of their etiology. Numerous cases point to the link between herpes simplex virus (HSV) infection and multifocal CNS demyelination in humans; however, convincing evidence from animal models has been missing. In this work, we found that HSV-1 infection of the cotton rat via a common route (lip abrasion) can cause multifocal CNS demyelination and inflammation. Remyelination occurred shortly after demyelination in HSV-1-infected cotton rats but could be incomplete, resulting in "scars," further supporting an association between HSV-1 infection and multifocal demyelinating disorders. Virus was detected sequentially in the lip, trigeminal ganglia, and brain of infected animals. Brain pathology developed primarily on the ipsilateral side of the brain stem, in the cerebellum, and contralateral side of the forebrain/midbrain, suggesting that the changes may ascend along the trigeminal lemniscus pathway. Neurologic defects occasionally detected in infected animals (e.g., defective whisker touch and blink responses and compromised balance) could be representative of the brain stem/cerebellum dysfunction. Immunization of cotton rats with a split HSV-1 vaccine protected animals against viral replication and brain pathology, suggesting that vaccination against HSV-1 may protect against demyelinating disorders. Our work demonstrates for the first time a direct association between infection with herpes simplex virus 1, a ubiquitous human pathogen generally associated with facial cold sores, and multifocal brain demyelination in an otherwise normal host, the cotton rat For a long time, demyelinating diseases were considered to be autoimmune in nature and were studied by indirect methods, such as immunizing animals with myelin components or feeding them toxic substances that induce demyelination. Treatment against demyelinating diseases has been elusive, partially because of their unknown etiology. This work provides the first experimental evidence for the role of HSV-1 as the etiologic agent of multifocal brain demyelination in a normal host and suggests that vaccination against HSV-1 can help to combat demyelinating disorders.
脱髓鞘中枢神经系统 (CNS) 疾病，如多发性硬化症 (MS) 和急性播散性脑脊髓炎 (ADEM)，由于对其病因缺乏了解，因此一直难以研究和治疗。许多病例表明单纯疱疹病毒 (HSV) 感染与人类多发性 CNS 脱髓鞘之间存在关联；然而，动物模型中缺乏令人信服的证据。在这项工作中，我们发现通过常见途径（唇部擦伤）感染单纯疱疹病毒 1 型 (HSV-1) 可导致棉鼠多发性 CNS 脱髓鞘和炎症。在 HSV-1 感染的棉鼠中，脱髓鞘后不久即可发生髓鞘再生，但可能不完全，导致“疤痕”，进一步支持 HSV-1 感染与多发性脱髓鞘疾病之间的关联。病毒依次在感染动物的唇部、三叉神经节和大脑中被检测到。脑病理学主要在脑干、小脑和大脑前脑/中脑的对侧发展，表明这些变化可能沿着三叉神经丘索通路上升。在感染动物中偶尔检测到的神经缺陷（例如，胡须触觉和眨眼反应受损以及平衡能力受损）可能代表脑干/小脑功能障碍。用 HSV-1 分裂疫苗对棉鼠进行免疫接种可保护动物免受病毒复制和脑病理学的影响，这表明接种 HSV-1 可能有助于预防脱髓鞘疾病。我们的工作首次证明了单纯疱疹病毒 1 型（一种普遍存在于人类的病原体，通常与面部疱疹有关）感染与正常宿主棉鼠的多发性脑脱髓鞘之间存在直接关联。长期以来，脱髓鞘疾病被认为是自身免疫性疾病，通过间接方法进行研究，例如用髓鞘成分免疫动物或用诱导脱髓鞘的有毒物质喂养它们。针对脱髓鞘疾病的治疗一直难以捉摸，部分原因是其病因不明。这项工作提供了单纯疱疹病毒 1 型作为正常宿主多发性脑脱髓鞘的病因的第一个实验证据，并表明接种 HSV-1 疫苗有助于对抗脱髓鞘疾病。
