Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA.
Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, USA
mBio. 2019 Mar 5;10(2):e02567-18. doi: 10.1128/mBio.02567-18.
Interferons (IFNs) and autophagy are critical neuronal defenses against viral infection. IFNs alter neuronal autophagy by promoting the accumulation of IFN-dependent LC3-decorated autophagic structures, termed LC3 clusters. Here, we analyzed LC3 clusters in sensory ganglia following herpes simplex virus 1 (HSV-1) infection. In the vicinity of acutely infected neurons, antigen-negative neurons contained structures resembling accumulated autophagosomes and autolysosomes that culminated in LC3 clusters. This accumulation reflects a delayed completion of autophagy. The ndosomal orting omplexes equired for ransport (ESCRT) machinery participates in autophagosome closure and is also required for HSV-1 replication. In this study, our results showed that HSV-1 infection and in primary neurons caused a decrease in Vps4 (a key ESCRT pathway ATPase) RNA and protein with concomitant Stat1 activation and LC3 cluster induction. We also observed that IFNs were sufficient to decrease RNA and protein levels of Vps4 in primary neurons and in other cell types. The accumulation of ubiquitin was also observed at the LC3 cluster sites. Together, our results show that IFNs modulate the ESCRT machinery in neurons in response to HSV-1 infections. Neurons rely on IFNs and autophagy as major defenses against viral infections, and HSV must overcome such defenses in order to replicate. In addition to controlling host immunity, HSV must also control host membranes in order to complete its life cycle. HSV uses the host ESCRT membrane scission machinery for viral production and transport. Here we present evidence of a new IFN-dependent mechanism used by the host to prevent ESCRT subversion by HSV. This activity also impacts the dynamics of autophagy, possibly explaining the presence of recently described LC3 clusters in the HSV-infected nervous system. The induced accumulations of ubiquitin observed in these LC3 clusters resembled those observed in certain neurodegenerative diseases, suggesting possible mechanistic parallels between these conditions.
干扰素 (IFNs) 和自噬是神经元抵抗病毒感染的关键防御机制。IFNs 通过促进 IFN 依赖性 LC3 标记的自噬结构（称为 LC3 聚集体）的积累来改变神经元自噬。在这里，我们分析了单纯疱疹病毒 1 (HSV-1) 感染后感觉神经节中的 LC3 聚集体。在急性感染神经元附近，抗原阴性神经元包含类似于积累的自噬体和自溶体的结构，最终形成 LC3 聚集体。这种积累反映了自噬的延迟完成。内体分选复合物所需的运输（ESCRT）机制参与自噬体的闭合，也是 HSV-1 复制所必需的。在这项研究中，我们的结果表明，HSV-1 感染和原代神经元导致关键 ESCRT 途径 ATP 酶 Vps4 的 RNA 和蛋白减少，同时伴有 Stat1 激活和 LC3 聚集体诱导。我们还观察到 IFNs 足以降低原代神经元和其他细胞类型中 Vps4 的 RNA 和蛋白水平。LC3 聚集体部位也观察到泛素的积累。总之，我们的结果表明，IFNs 调节神经元中的 ESCRT 机制以响应 HSV-1 感染。神经元依赖 IFNs 和自噬作为抵抗病毒感染的主要防御机制，而 HSV 必须克服这种防御才能复制。除了控制宿主免疫外，HSV 还必须控制宿主膜以完成其生命周期。HSV 使用宿主 ESCRT 膜分裂机制进行病毒产生和运输。在这里，我们提供了宿主用于防止 HSV 颠覆 ESCRT 的新 IFN 依赖性机制的证据。这种活性还影响自噬的动态，可能解释了在 HSV 感染的神经系统中最近描述的 LC3 聚集体的存在。在这些 LC3 聚集体中观察到的诱导性泛素积累类似于在某些神经退行性疾病中观察到的积累，表明这些疾病之间可能存在机制相似性。
