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

Liuliu Yang; Yuling Han; Ting Zhou; Lauretta A Lacko; Mohsan Saeed; Christina Tan; Ron Danziger; Jiajun Zhu; Zeping Zhao; Clare Cahir; Alice Maria Giani; Yang Li; Xue Dong; Dorota Moroziewicz; NYSCF Global Stem Cell Array® Team; Daniel Paull; Zhengming Chen; Aaron Zhong; Scott A Noggle; Charles M Rice; Qibin Qi; Todd Evans; Shuibing Chen

doi:10.1016/j.isci.2023.107001

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

iScience. 2023 May 29;26(7):107001. doi: 10.1016/j.isci.2023.107001. eCollection 2023 Jul 21.

Authors

Liuliu Yang^{1

2}, Yuling Han^{1

2}, Ting Zhou^{1

3}, Lauretta A Lacko¹, Mohsan Saeed^{4

5

6}, Christina Tan¹, Ron Danziger¹, Jiajun Zhu^{1

2}, Zeping Zhao^{1

2}, Clare Cahir¹, Alice Maria Giani¹, Yang Li⁷, Xue Dong¹, Dorota Moroziewicz⁸; NYSCF Global Stem Cell Array® Team; Daniel Paull⁸, Zhengming Chen⁹, Aaron Zhong³, Scott A Noggle⁸, Charles M Rice⁴, Qibin Qi⁷, Todd Evans^{1

2}, Shuibing Chen^{1

2}

Affiliations

¹ Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
² Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
³ Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
⁴ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
⁵ Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA.
⁶ National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA.
⁷ Department of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
⁸ The New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3Road Floor, New York, NY 10019, USA.
⁹ Department of Population Health Sciences, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.

Abstract

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.

Keywords: Stem cells research; Virology.

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States