Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
Department of Biochemistry and Molecular Biology, Sealy Institute for Drug Discovery, Department of Pharmacology and Toxicology and Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.
Cell Rep. 2022 Apr 12;39(2):110655. doi: 10.1016/j.celrep.2022.110655.
Zika virus (ZIKV) and dengue virus (DENV) are arthropod-borne pathogenic flaviviruses that co-circulate in many countries. To understand some of the pressures that influence ZIKV evolution, we mimic the natural transmission cycle by repeating serial passaging of ZIKV through cultured mosquito cells and either DENV-naive or DENV-immune mice. Compared with wild-type ZIKV, the strains passaged under both conditions exhibit increased pathogenesis in DENV-immune mice. Application of reverse genetics identifies an isoleucine-to-valine mutation (I39V) in the NS2B proteins of both passaged strains that confers enhanced fitness and escape from pre-existing DENV immunity. Introduction of I39V or I39T, a naturally occurring homologous mutation detected in recent ZIKV isolates, increases the replication of wild-type ZIKV in human neuronal precursor cells and laboratory-raised mosquitoes. Our data indicate that ZIKV strains with enhanced transmissibility and pathogenicity can emerge in DENV-naive or -immune settings, and that NS2B-I39 mutants may represent ZIKV variants of interest.
寨卡病毒（ZIKV）和登革热病毒（DENV）是两种虫媒传播的致病性黄病毒，在许多国家共同传播。为了了解影响 ZIKV 进化的一些压力，我们通过在培养的蚊子细胞和 DENV 未感染或免疫的小鼠中重复进行 ZIKV 的连续传代，模拟自然传播周期。与野生型 ZIKV 相比，在这两种条件下传代的毒株在 DENV 免疫小鼠中表现出更高的致病性。应用反向遗传学方法鉴定出两种传代株的 NS2B 蛋白中的异亮氨酸到缬氨酸突变（I39V），该突变赋予了更高的适应性并逃避了预先存在的 DENV 免疫力。引入 I39V 或 I39T，一种在最近的 ZIKV 分离株中检测到的天然同源突变，可增加野生型 ZIKV 在人神经前体细胞和实验室饲养的蚊子中的复制。我们的数据表明，在 DENV 未感染或免疫的情况下，具有增强传染性和致病性的 ZIKV 株可能会出现，并且 NS2B-I39 突变体可能代表 ZIKV 感兴趣的变体。
