Anfasa Fatih, Siegers Jurre Y, van der Kroeg Mark, Mumtaz Noreen, Stalin Raj V, de Vrij Femke M S, Widagdo W, Gabriel Gülsah, Salinas Sara, Simonin Yannick, Reusken Chantal, Kushner Steven A, Koopmans Marion P G, Haagmans Bart, Martina Byron E E, van Riel Debby
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
mSphere. 2017 Jul 26;2(4). doi: 10.1128/mSphere.00292-17. eCollection 2017 Jul-Aug.
Recent Zika virus (ZIKV) infections have been associated with a range of neurological complications, in particular congenital microcephaly. Human neural progenitor cells (hNPCs) are thought to play an important role in the pathogenesis of microcephaly, and experimental ZIKV infection of hNPCs has been shown to induce cell death. However, the infection efficiency and rate of cell death have varied between studies, which might be related to intrinsic differences between African and Asian lineage ZIKV strains. Therefore, we determined the replication kinetics, including infection efficiency, burst size, and ability to induce cell death, of two Asian and two African ZIKV strains. African ZIKV strains replicated to higher titers in Vero cells, human glioblastoma (U87MG) cells, human neuroblastoma (SK-N-SH) cells, and hNPCs than Asian ZIKV strains. Furthermore, infection with Asian ZIKV strains did not result in significant cell death early after infection, whereas infection with African ZIKV strains resulted in high percentages of cell death in hNPCs. The differences between African and Asian lineage ZIKV strains highlight the importance of including relevant ZIKV strains to study the pathogenesis of congenital microcephaly and caution against extrapolation of experimental data obtained using historical African ZIKV strains to the current outbreak. Finally, the fact that Asian ZIKV strains infect only a minority of cells with a relatively low burst size together with the lack of early cell death induction might contribute to its ability to cause chronic infections within the central nervous system (CNS). The mechanism by which ZIKV causes a range of neurological complications, especially congenital microcephaly, is not well understood. The fact that congenital microcephaly is associated with Asian lineage ZIKV strains raises the question of why this was not discovered earlier. One possible explanation is that Asian and African ZIKV strains differ in their abilities to infect cells of the CNS and to cause neurodevelopmental problems. Here, we show that Asian ZIKV strains infect and induce cell death in human neural progenitor cells-which are important target cells in the development of congenital microcephaly-less efficiently than African ZIKV strains. These features of Asian ZIKV strains likely contribute to their ability to cause chronic infections, often observed in congenital microcephaly cases. It is therefore likely that phenotypic differences between ZIKV strains could be, at least in part, responsible for the ability of Asian ZIKV strains to cause congenital microcephaly.
近期寨卡病毒（ZIKV）感染与一系列神经并发症相关，尤其是先天性小头畸形。人类神经祖细胞（hNPCs）被认为在小头畸形的发病机制中起重要作用，并且实验表明hNPCs感染ZIKV可诱导细胞死亡。然而，不同研究之间的感染效率和细胞死亡率有所不同，这可能与非洲系和亚洲系ZIKV毒株之间的内在差异有关。因此，我们测定了两株亚洲ZIKV毒株和两株非洲ZIKV毒株的复制动力学，包括感染效率、爆发量以及诱导细胞死亡的能力。非洲ZIKV毒株在非洲绿猴肾（Vero）细胞、人胶质母细胞瘤（U87MG）细胞、人神经母细胞瘤（SK-N-SH）细胞和hNPCs中的复制滴度高于亚洲ZIKV毒株。此外，感染亚洲ZIKV毒株在感染早期并未导致明显的细胞死亡，而感染非洲ZIKV毒株则导致hNPCs中高比例的细胞死亡。非洲系和亚洲系ZIKV毒株之间的差异凸显了纳入相关ZIKV毒株来研究先天性小头畸形发病机制的重要性，并警示不要将使用历史上非洲ZIKV毒株获得的实验数据外推至当前疫情。最后，亚洲ZIKV毒株仅感染少数细胞且爆发量相对较低，同时缺乏早期细胞死亡诱导，这一事实可能有助于其在中枢神经系统（CNS）内引发慢性感染。ZIKV导致一系列神经并发症，尤其是先天性小头畸形的机制尚不清楚。先天性小头畸形与亚洲系ZIKV毒株相关这一事实引发了为何此前未被发现的问题。一种可能的解释是，亚洲和非洲ZIKV毒株在感染CNS细胞以及引起神经发育问题的能力方面存在差异。在此，我们表明亚洲ZIKV毒株在人类神经祖细胞（先天性小头畸形发育过程中的重要靶细胞）中的感染和诱导细胞死亡效率低于非洲ZIKV毒株。亚洲ZIKV毒株的这些特征可能有助于其引发慢性感染，这在先天性小头畸形病例中经常观察到。因此，ZIKV毒株之间的表型差异可能至少部分地导致了亚洲ZIKV毒株导致先天性小头畸形的能力。
