Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
Arthropod-Borne Animal Disease Research Unit, Center for Grain and Animal Health Research, Agricultural Research Service, United States Department of Agriculture, Manhattan, Kansas, USA.
mBio. 2023 Apr 25;14(2):e0360622. doi: 10.1128/mbio.03606-22. Epub 2023 Feb 21.
Powassan infection is caused by two closely related, tick-transmitted viruses of the genus (family ): Powassan virus lineage I (POWV) and lineage II (known as deer tick virus [DTV]). Infection is typically asymptomatic or mild but can progress to neuroinvasive disease. Approximately 10% of neuroinvasive cases are fatal, and half of the survivors experience long-term neurological sequelae. Understanding how these viruses cause long-term symptoms as well as the possible role of viral persistence is important for developing therapies. We intraperitoneally inoculated 6-week-old C57BL/6 mice (50% female) with 10 focus-forming units (FFU) DTV and assayed for infectious virus, viral RNA, and inflammation during acute infection and 21, 56, and 84 days postinfection (dpi). Although most mice (86%) were viremic 3 dpi, only 21% of the mice were symptomatic and 83% recovered. Infectious virus was detected only in the brains of mice sampled during the acute infection. Viral RNA was detected in the brain until 84 dpi, but the magnitude decreased over time. Meningitis and encephalitis were visible in acute mice and from mice sampled at 21 dpi. Inflammation was observed until 56 dpi in the brain and 84 dpi in the spinal cord, albeit at low levels. These results suggest that the long-term neurological symptoms associated with Powassan disease are likely caused by lingering viral RNA and chronic inflammation in the central nervous system rather than by a persistent, active viral infection. The C57BL/6 model of persistent Powassan mimics illness in humans and can be used to study the mechanisms of chronic disease. Half of Powassan infection survivors experience long-term, mild to severe neurological symptoms. The progression from acute to chronic Powassan disease is not well understood, severely limiting treatment and prevention options. Infection of C57BL/6 mice with DTV mimics clinical disease in humans, and the mice exhibit CNS inflammation and viral RNA persistence until at least 86 dpi, while infectious virus is undetectable after 12 dpi. These findings suggest that the long-term neurological symptoms of chronic Powassan disease are in part due the persistence of viral RNA and the corresponding long-term inflammation of the brain and spinal cord. Our work demonstrates that C57BL/6 mice can be used to study the pathogenesis of chronic Powassan disease.
波瓦桑感染是由两种密切相关的蜱传病毒引起的，属于 （科）：波瓦桑病毒 I 谱系（POWV）和 II 谱系（称为鹿蜱病毒[DTV]）。感染通常无症状或轻度，但可进展为神经侵袭性疾病。大约 10%的神经侵袭性病例是致命的，一半的幸存者有长期的神经后遗症。了解这些病毒如何导致长期症状以及病毒持续存在的可能作用对于开发疗法很重要。我们用 10 个焦点形成单位（FFU）DTV 经腹腔接种 6 周龄 C57BL/6 小鼠（50%雌性），并在急性感染和感染后 21、56 和 84 天检测传染性病毒、病毒 RNA 和炎症。尽管大多数小鼠（86%）在 3dpi 时呈病毒血症，但只有 21%的小鼠出现症状，83%的小鼠恢复。仅在急性感染期间采样的小鼠的大脑中检测到传染性病毒。在 84dpi 时仍能检测到病毒 RNA，但随着时间的推移，其数量减少。在急性小鼠和 21dpi 采样的小鼠中可观察到脑膜炎和脑炎。在大脑中可观察到炎症，直到 56dpi，在脊髓中可观察到炎症，直到 84dpi，但水平较低。这些结果表明，与波瓦桑病相关的长期神经症状可能是由中枢神经系统中持续存在的病毒 RNA 和慢性炎症引起的，而不是由持续的、活跃的病毒感染引起的。C57BL/6 持续性波瓦桑模型模拟了人类的疾病，可用于研究慢性疾病的机制。 一半的波瓦桑感染幸存者经历长期、轻度至重度神经症状。从急性到慢性波瓦桑疾病的进展尚不清楚，严重限制了治疗和预防选择。DTV 感染 C57BL/6 小鼠可模拟人类临床疾病，且小鼠至少在 86dpi 时表现出中枢神经系统炎症和病毒 RNA 持续存在，而在 12dpi 后无法检测到传染性病毒。这些发现表明，慢性波瓦桑病的长期神经症状部分是由于病毒 RNA 的持续存在以及大脑和脊髓的相应长期炎症。我们的工作表明，C57BL/6 小鼠可用于研究慢性波瓦桑病的发病机制。
