Sección Inmunología, Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, España.
J Neuroinflammation. 2020 Dec 7;17(1):371. doi: 10.1186/s12974-020-02044-4.
Genetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD). However, the number of cases caused exclusively by genetic alterations is low, suggesting an important contribution of environmental factors to NDDs. Among these factors, viruses like herpes simplex viruses (HSV-2), capable of establishing lifelong infections within the nervous system (NS), are being proposed to have a role in NDDs. Despite promising data, there is a significant lack of knowledge on this and an urgent need for more research.
We have set up a mouse model to study HSV latency and its associated neuroinflammation in the spinal cord. The goal of this model was to observe neuroinflammatory changes caused by HSV latent infections, and if those changes were similar to alterations observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients.
In infected spinal cords, we have observed a strong leukocyte infiltration and a severe alteration of microglia close to motor neurons. We have also analyzed ALS-related proteins: we have not found changes in TDP-43 and Fus in neurons, but interestingly, we have found decreased protein levels of C9orf72, of which coding gene is severely altered in some familial forms of ALS and is critical for microglia homeostasis.
Latent infection of HSV in the spinal cord showed altered microglia and leukocyte infiltration. These inflammatory features resembled to those observed in the spinal cord of ALS patients. No changes mimicking ALS neuropathology, such as TDP-43 cytoplasmic inclusions, were found in infected spinal cords, but a decrease in protein levels of C9orf72 was observed. Then, further studies should be required to determine whether HSV-2 has a role in ALS.
遗传学为涉及神经退行性疾病（NDD）的潜在分子途径提供了线索。然而，仅由遗传改变引起的病例数量很少，这表明环境因素对 NDD 有重要贡献。在这些因素中，疱疹病毒（HSV-2）等能够在神经系统（NS）内建立终身感染的病毒，被认为在 NDD 中起作用。尽管有很有前景的数据，但对这方面的了解仍然很少，迫切需要更多的研究。
我们建立了一种小鼠模型来研究 HSV 潜伏及其在脊髓中的相关神经炎症。该模型的目的是观察 HSV 潜伏感染引起的神经炎症变化，以及这些变化是否与肌萎缩侧索硬化症（ALS）患者脊髓中的改变相似。
在感染的脊髓中，我们观察到强烈的白细胞浸润和靠近运动神经元的小胶质细胞严重改变。我们还分析了与 ALS 相关的蛋白质：我们没有在神经元中发现 TDP-43 和 Fus 的变化，但有趣的是，我们发现 C9orf72 的蛋白水平降低，其编码基因在一些家族性 ALS 中严重改变，对小胶质细胞稳态至关重要。
HSV 在脊髓中的潜伏感染显示出小胶质细胞和白细胞浸润的改变。这些炎症特征与 ALS 患者脊髓中观察到的相似。在感染的脊髓中未发现类似 ALS 神经病理学的变化，如 TDP-43 细胞质包涵体，但观察到 C9orf72 的蛋白水平降低。然后，需要进一步研究以确定 HSV-2 是否在 ALS 中起作用。
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