小胶质细胞,中枢神经系统的常驻巨噬细胞,越来越被认为有助于人类发展的各个方面,健康,和疾病。近年来,在小鼠和人类模型中的大量研究已经确定小胶质细胞是嗜神经病毒感染进展中的“双刃剑”:在某些情况下防止病毒复制和细胞死亡,同时充当病毒储库并促进其他细胞的过度应激和细胞毒性。必须了解人类小胶质细胞反应的多样性,以便在治疗上调节它们;然而,由于先天免疫的种间差异和体外培养后的快速转化,人类小胶质细胞的建模历来具有挑战性。在这次审查中,我们讨论了小胶质细胞对关键亲神经病毒感染的神经发病机理的贡献:人类免疫缺陷病毒1(HIV-1),寨卡病毒(ZIKV),日本脑炎病毒(JEV),西尼罗河病毒(WNV)单纯疱疹病毒(HSV),和严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)。我们特别关注人类干细胞衍生的小胶质细胞的最新工作,并提出了利用这些强大模型进一步揭示物种和疾病特异性小胶质细胞反应以及针对嗜神经病毒感染的新型治疗干预措施的策略。
Microglia, the resident macrophage of the central nervous system, are increasingly recognized as contributing to diverse aspects of human development, health, and disease. In recent years, numerous studies in both mouse and human models have identified microglia as a \"double edged sword\" in the progression of neurotropic viral infections: protecting against viral replication and cell death in some contexts, while acting as viral reservoirs and promoting excess cellular stress and cytotoxicity in others. It is imperative to understand the diversity of human microglial responses in order to therapeutically modulate them; however, modeling human microglia has been historically challenging due to significant interspecies differences in innate immunity and rapid transformation upon in vitro culture. In this review, we discuss the contribution of microglia to the neuropathogenesis of key neurotropic viral infections: human immunodeficiency virus 1 (HIV-1), Zika virus (ZIKV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Herpes simplex virus (HSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We pay special attention to recent work with human stem cell-derived microglia and propose strategies to leverage these powerful models to further uncover species- and disease-specific microglial responses and novel therapeutic interventions for neurotropic viral infections.