Institute of Medical Microbiology and Virology, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany.
Institute of Biochemistry, Berlin Institute of Health (BIH) and Charité -Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
Int J Mol Sci. 2021 Jan 27;22(3):1220. doi: 10.3390/ijms22031220.
The association of members of the enterovirus family with pregnancy complications up to miscarriages is under discussion. Here, infection of two different human induced pluripotent stem cell (iPSC) lines and iPSC-derived primary germ-layer cells with coxsackievirus B3 (CVB3) was characterized as an in vitro cell culture model for very early human development. Transcriptomic analysis of iPSC lines infected with recombinant CVB3 expressing enhanced green fluorescent protein (EGFP) revealed a reduction in the expression of pluripotency genes besides an enhancement of genes involved in RNA metabolism. The initial distribution of CVB3-EGFP-positive cells within iPSC colonies correlated with the distribution of its receptor coxsackie- and adenovirus receptor (CAR). Application of anti-CAR blocking antibodies supported the requirement of CAR, but not of the co-receptor decay-accelerating factor (DAF) for infection of iPSC lines. Among iPSC-derived germ-layer cells, mesodermal cells were especially vulnerable to CVB3-EGFP infection. Our data implicate further consideration of members of the enterovirus family in the screening program of human pregnancies. Furthermore, iPSCs with their differentiation capacity into cell populations of relevant viral target organs could offer a reliable screening approach for therapeutic intervention and for assessment of organ-specific enterovirus virulence.
肠道病毒家族成员与妊娠并发症（包括流产）的关联正在讨论之中。在这里，我们将柯萨奇病毒 B3（CVB3）感染两种不同的人诱导多能干细胞（iPSC）系和 iPSC 衍生的原肠胚层细胞作为体外细胞培养模型，用于研究人类早期发育。用表达增强型绿色荧光蛋白（EGFP）的重组 CVB3 感染 iPSC 系的转录组分析显示，除了 RNA 代谢相关基因的增强外，多能性基因的表达也降低了。在 iPSC 集落中感染的 CVB3-EGFP 阳性细胞的初始分布与细胞表面病毒受体柯萨奇病毒和腺病毒受体（CAR）的分布相关。抗 CAR 阻断抗体的应用支持 CAR 的作用，但不支持辅助受体衰变加速因子（DAF）在 iPSC 系感染中的作用。在 iPSC 衍生的原肠胚层细胞中，中胚层细胞特别容易受到 CVB3-EGFP 的感染。我们的数据提示需要进一步考虑肠道病毒家族成员在人类妊娠筛查计划中的作用。此外，具有分化为相关病毒靶器官细胞群体能力的 iPSCs 可以为治疗干预和评估器官特异性肠道病毒毒力提供可靠的筛选方法。
