Isogenic human trophectoderm cells demonstrate the role of NDUFA4 and associated variants in ZIKV infection,iScience

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Isogenic human trophectoderm cells demonstrate the role of NDUFA4 and associated variants in ZIKV infection
iScience ( IF 4.6 ) Pub Date : 2023-05-29 , DOI: 10.1016/j.isci.2023.107001
Liuliu Yang _{1,

2} , Yuling Han _{1,

2} , Ting Zhou _{1,

3} , Lauretta A Lacko ₁ , Mohsan Saeed _{4,

5,

6} , Christina Tan ₁ , Ron Danziger ₁ , Jiajun Zhu _{1,

2} , Zeping Zhao _{1,

2} , Clare Cahir ₁ , Alice Maria Giani ₁ , Yang Li ₇ , Xue Dong ₁ , Dorota Moroziewicz ₈ , , Daniel Paull ₈ , Zhengming Chen ₉ , Aaron Zhong ₃ , Scott A Noggle ₈ , Charles M Rice ₄ , Qibin Qi ₇ , Todd Evans _{1,

2} , Shuibing Chen _{1,

2}

Affiliation

Population-based genome-wide association studies (GWAS) normally require a large sample size, which can be labor intensive and costly. Recently, we reported a human induced pluripotent stem cell (hiPSC) array-based GWAS method, identifying NDUFA4 as a host factor for Zika virus (ZIKV) infection. In this study, we extended our analysis to trophectoderm cells, which constitute one of the major routes of mother-to-fetus transmission of ZIKV during pregnancy. We differentiated hiPSCs from various donors into trophectoderm cells. We then infected cells carrying loss of function mutations in NDUFA4, harboring risk versus non-risk alleles of SNPs (rs917172 and rs12386620) or having deletions in the NDUFA4 cis-regulatory region with ZIKV. We found that loss/reduction of NDUFA4 suppressed ZIKV infection in trophectoderm cells. This study validated our published hiPSC array-based system as a useful platform for GWAS and confirmed the role of NDUFA4 as a susceptibility locus for ZIKV in disease-relevant trophectoderm cells.

中文翻译：

同基因人滋养外胚层细胞证明 NDUFA4 和相关变体在 ZIKV 感染中的作用

基于人群的全基因组关联研究（GWAS）通常需要较大的样本量，这可能是劳动密集型且成本高昂的。最近，我们报道了一种基于人诱导多能干细胞（hiPSC）阵列的 GWAS 方法，该方法确定 NDUFA4 是寨卡病毒（ZIKV）感染的宿主因子。在这项研究中，我们将分析扩展到滋养外胚层细胞，该细胞构成了妊娠期间 ZIKV 母婴传播的主要途径之一。我们将来自不同供体的 hiPSCs 分化为滋养外胚层细胞。然后，我们感染了携带 NDUFA4 功能丧失突变的细胞，与 SNP （rs917172 和 rs12386620）的风险等位基因相比，这些细胞在 NDUFA4 顺式调节区具有缺失，并且 ZIKV 具有 ZIKV。我们发现 NDUFA4 的缺失/减少抑制了滋养外胚层细胞中的 ZIKV 感染。本研究验证了我们发表的基于 hiPSC 阵列的系统作为 GWAS 的有用平台，并证实了 NDUFA4 作为疾病相关滋养外胚层细胞中 ZIKV 易感位点的作用。

更新日期：2023-05-29

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