Neuroscience and Mental Health Institute, University of Albertagrid.17089.37, Edmonton, Alberta, Canada.
Department of Medicine, University of Albertagrid.17089.37, Edmonton, Alberta, Canada.
J Virol. 2021 Nov 9;95(23):e0107421. doi: 10.1128/JVI.01074-21. Epub 2021 Sep 15.
Human pegivirus (HPgV) infects peripheral leukocytes but was recently shown to be a neurotropic virus associated with leukoencephalitis in humans. In the present study, we investigated the neural cell tropism of HPgV as well as its effects on host immune responses. HPgV wild type (WT) and a mutant virus with a deletion in the HPgV gene (ΔNS2) were able to productively infect human astrocytes and microglia but not neurons or an oligodendrocyte-derived cell line. Of note, the ΔNS2 virus replicated better than WT pegivirus in astrocytes, with both viruses being able to subsequently infect and spread in fresh human astrocyte cultures. Infection of human glia by HPgV WT and ΔNS2 viruses resulted in suppression of peroxisome-associated genes, including , , , , , and , during peak viral production, which was accompanied by reduced expression of , , , and , particularly in ΔNS2-infected cells. These data were consistent with analyses of brain tissue from patients infected with HPgV in which we observed suppression of peroxisome and type I interferon gene transcripts, including , , , and , with concurrent loss of PMP70 immunoreactivity in glia. Our data indicate that human astrocytes and microglia are permissive to HPgV infection, resulting in peroxisome injury and suppressed antiviral signaling that is influenced by viral diversity. Human pegiviruses are detected in 1 to 5% of the general population, principally infecting leukocytes, although their effects on human health remain uncertain. Here, we show that human pegivirus infects specific neural cell types in culture and human brain and, like other neurotropic flaviviruses, causes suppression of peroxisome and antiviral signaling pathways, which could favor ongoing viral infection and perhaps confer susceptibility to the development of neurological disease.
人类细小病毒（HPgV）感染外周白细胞，但最近发现它是一种与人类脑炎相关的神经嗜性病毒。在本研究中，我们研究了 HPgV 的神经细胞嗜性及其对宿主免疫反应的影响。HPgV 野生型（WT）和基因缺失突变体（ΔNS2）均能有效地感染人星形胶质细胞和小胶质细胞，但不能感染神经元或少突胶质细胞来源的细胞系。值得注意的是，与 WT 肝炎病毒相比，ΔNS2 病毒在星形胶质细胞中的复制能力更强，两种病毒随后都能够感染并在新鲜的人星形胶质细胞培养物中传播。HPgV WT 和 ΔNS2 病毒感染人神经胶质细胞后，过氧化物酶体相关基因（包括 、 、 、 、 和 ）的表达受到抑制，在病毒大量复制时尤其如此，同时 、 、 和 的表达也减少，尤其是在感染 ΔNS2 的细胞中。这些数据与感染 HPgV 的患者脑组织分析结果一致，我们观察到过氧化物酶体和 I 型干扰素基因转录物（包括 、 、 和 ）受到抑制，同时胶质细胞中的 PMP70 免疫反应性丧失。我们的数据表明，人星形胶质细胞和小胶质细胞对 HPgV 感染具有易感性，导致过氧化物酶体损伤和抗病毒信号转导受抑制，这可能受到病毒多样性的影响。人类细小病毒在 1%至 5%的普通人群中被检测到，主要感染白细胞，但它们对人类健康的影响仍不确定。在这里，我们显示 HPgV 感染培养中的特定神经细胞类型和人脑，并且与其他神经嗜性黄病毒一样，引起过氧化物酶体和抗病毒信号通路的抑制，这可能有利于持续的病毒感染，并可能导致易患神经疾病。
