Microbiology Department, Institute of Biomedical Sciences (ICB-II), University of São Paulo, Av. Prof Lineu Prestes, 1374, 2Nd Floor, Room 235, São Paulo, SP, 05508-000, Brazil.
Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo-SP, 01246-903, Brazil.
Sci Rep. 2024 Aug 3;14(1):18002. doi: 10.1038/s41598-024-65392-8.
Zika virus (ZIKV) infection was first reported in 2015 in Brazil as causing microcephaly and other developmental abnormalities in newborns, leading to the identification of Congenital Zika Syndrome (CZS). Viral infections have been considered an environmental risk factor for neurodevelopmental disorders outcome, such as Autism Spectrum Disorder (ASD). Moreover, not only the infection per se, but maternal immune system activation during pregnancy, has been linked to fetal neurodevelopmental disorders. To understand the impact of ZIKV vertical infection on brain development, we derived induced pluripotent stem cells (iPSC) from Brazilian children born with CZS, some of the patients also being diagnosed with ASD. Comparing iPSC-derived neurons from CZS with a control group, we found lower levels of pre- and postsynaptic proteins and reduced functional synapses by puncta co-localization. Furthermore, neurons and astrocytes derived from the CZS group showed decreased glutamate levels. Additionally, the CZS group exhibited elevated levels of cytokine production, one of which being IL-6, already associated with the ASD phenotype. These preliminary findings suggest that ZIKV vertical infection may cause long-lasting disruptions in brain development during fetal stages, even in the absence of the virus after birth. These disruptions could contribute to neurodevelopmental disorders manifestations such as ASD. Our study contributes with novel knowledge of the CZS outcomes and paves the way for clinical validation and the development of potential interventions to mitigate the impact of ZIKV vertical infection on neurodevelopment.
寨卡病毒（ZIKV）感染于 2015 年在巴西首次报道，可导致新生儿小头畸形和其他发育异常，从而确定了先天性寨卡综合征（CZS）。病毒感染被认为是神经发育障碍结局的环境风险因素，如自闭症谱系障碍（ASD）。此外，不仅感染本身，而且妊娠期间母体免疫系统的激活，与胎儿神经发育障碍有关。为了了解 ZIKV 垂直感染对大脑发育的影响，我们从巴西患有 CZS 的儿童中诱导多能干细胞（iPSC），其中一些患者也被诊断为 ASD。将 CZS 患者的 iPSC 衍生神经元与对照组进行比较，我们发现前突触和后突触蛋白水平较低，通过突触点共定位减少了功能性突触。此外，来自 CZS 组的神经元和星形胶质细胞表现出降低的谷氨酸水平。此外，CZS 组表现出细胞因子产生水平升高，其中一种细胞因子是 IL-6，已经与 ASD 表型相关。这些初步发现表明，ZIKV 垂直感染可能在胎儿期导致大脑发育的持久破坏，即使在出生后病毒不存在也是如此。这些破坏可能导致神经发育障碍的表现，如 ASD。我们的研究为 CZS 结果提供了新的知识，并为临床验证和开发潜在干预措施以减轻 ZIKV 垂直感染对神经发育的影响铺平了道路。
