Chandwani Manisha N, Kamte Yashika S, Singh Vivek R, Hemerson Marlo E, Michaels Alexa C, Leak Rehana K, O'Donnell Lauren A
Duquesne University School of Pharmacy, Graduate School of Pharmaceutical Sciences, Pittsburgh, PA, USA.
Duquesne University School of Pharmacy, Graduate School of Pharmaceutical Sciences, Pittsburgh, PA, USA.
Brain Behav Immun. 2023 Nov;114:61-77. doi: 10.1016/j.bbi.2023.07.008. Epub 2023 Jul 28.
Viruses induce a wide range of neurological sequelae through the dysfunction and death of infected cells and persistent inflammation in the brain. Neural stem cells (NSCs) are often disturbed during viral infections. Although some viruses directly infect and kill NSCs, the antiviral immune response may also indirectly affect NSCs. To better understand how NSCs are influenced by a productive immune response, where the virus is successfully resolved and the host survives, we used the CD46+ mouse model of neuron-restricted measles virus (MeV) infection. As NSCs are spared from direct infection in this model, they serve as bystanders to the antiviral immune response initiated by selective infection of mature neurons. MeV-infected mice showed distinct regional and temporal changes in NSCs in the primary neurogenic niches of the brain, the hippocampus and subventricular zone (SVZ). Hippocampal NSCs increased throughout the infection (7 and 60 days post-infection; dpi), while mature neurons transiently declined at 7 dpi and then rebounded to basal levels by 60 dpi. In the SVZ, NSC numbers were unchanged, but mature neurons declined even after the infection was controlled at 60 dpi. Further analyses demonstrated sex, temporal, and region-specific changes in NSC proliferation and neurogenesis throughout the infection. A relatively long-term increase in NSC proliferation and neurogenesis was observed in the hippocampus; however, neurogenesis was reduced in the SVZ. This decline in SVZ neurogenesis was associated with increased immature neurons in the olfactory bulb in female, but not male mice, suggesting potential migration of newly-made neurons out of the female SVZ. These sex differences in SVZ neurogenesis were accompanied by higher infiltration of B cells and greater expression of interferon-gamma and interleukin-6 in female mice. Learning, memory, and olfaction tests revealed no overt behavioral changes after the acute infection subsided. These results indicate that antiviral immunity modulates NSC activity in adult mice without inducing gross behavioral deficits among those tested, suggestive of mechanisms to restore neurons and maintain adaptive behavior, but also revealing the potential for robust NSC disruption in subclinical infections.
病毒通过受感染细胞的功能障碍和死亡以及大脑中的持续炎症，引发广泛的神经后遗症。神经干细胞（NSCs）在病毒感染期间常常受到干扰。虽然一些病毒直接感染并杀死神经干细胞，但抗病毒免疫反应也可能间接影响神经干细胞。为了更好地了解在病毒成功清除且宿主存活的有效免疫反应中神经干细胞是如何受到影响的，我们使用了神经元限制性麻疹病毒（MeV）感染的CD46 +小鼠模型。由于在该模型中神经干细胞未受到直接感染，它们作为成熟神经元选择性感染引发的抗病毒免疫反应的旁观者。感染MeV的小鼠在大脑主要神经发生微环境、海马体和脑室下区（SVZ）的神经干细胞中表现出明显的区域和时间变化。在整个感染过程中（感染后7天和60天；dpi），海马体神经干细胞数量增加，而成熟神经元在7 dpi时短暂下降，然后在60 dpi时反弹至基础水平。在SVZ中，神经干细胞数量没有变化，但即使在感染在60 dpi得到控制后，成熟神经元数量仍在下降。进一步分析表明，在整个感染过程中，神经干细胞增殖和神经发生存在性别、时间和区域特异性变化。在海马体中观察到神经干细胞增殖和神经发生相对长期增加；然而，SVZ中的神经发生减少。SVZ神经发生的这种下降与雌性而非雄性小鼠嗅球中未成熟神经元的增加有关，表明新生成的神经元可能从雌性SVZ迁移出去。SVZ神经发生中的这些性别差异伴随着雌性小鼠中B细胞的更高浸润以及干扰素 - γ和白细胞介素 - 6的更高表达。学习、记忆和嗅觉测试显示，急性感染消退后没有明显的行为变化。这些结果表明，抗病毒免疫调节成年小鼠的神经干细胞活性，而不会在测试的小鼠中引起明显的行为缺陷，这暗示了恢复神经元和维持适应性行为的机制，但也揭示了亚临床感染中神经干细胞受到严重破坏的可能性。
