Journal
CELL STEM CELL
Volume 29, Issue 10, Pages 1475-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2022.09.008
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Funding
- NIDKK [DP3DK111907, R01DK116075, R01DK119667, R01 DK119667-02S1, R01 DK124463, R01DK130454-01, U01 DK127777]
- American Diabetes Association [7-20-COVID-211]
- Department of Surgery, Weill Cornell Medicine
- Bill and Melinda Gates Foundation
- Defense Advanced Research Projects Agency [W911NF-16-C-0050]
- Marc Haas Foundation
- NIAID [R01AI124690, R01AI091707]
- Mastercard Diversity-Mentorship Collaborative Research Assistance for Primary Parents Initiative
- Eunice Kennedy Shriver NICHD [1F32HD096810-01A 1]
- New York State Department of Health (NYSTEM) [C32599, C29156, C32591]
- NYSTEM Stem Cell Biology Scholar [DOH01-TRAIN3-2016-00004]
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This study demonstrates the use of human-induced pluripotent stem cells (hiPSCs) to link human genetics with viral infectivity. It identifies a cis-regulatory region of the NDUFA4 gene associated with susceptibility to Zika virus infection. Loss of NDUFA4 reduces sensitivity to multiple viral infections, and mechanistic studies reveal that loss/reduction of NDUFA4 induces mitochondrial stress and upregulation of interferon signaling.
Population-based studies to identify disease-associated risk alleles typically require samples from a large number of individuals. Here, we report a human-induced pluripotent stem cell (hiPSC)-based screening strat-egy to link human genetics with viral infectivity. A genome-wide association study (GWAS) identified a cluster of single-nucleotide polymorphisms (SNPs) in a cis-regulatory region of the NDUFA4 gene, which was asso-ciated with susceptibility to Zika virus (ZIKV) infection. Loss of NDUFA4 led to decreased sensitivity to ZIKV, dengue virus, and SARS-CoV-2 infection. Isogenic hiPSC lines carrying non-risk alleles of SNPs or deletion of the cis-regulatory region lower sensitivity to viral infection. Mechanistic studies indicated that loss/reduction of NDUFA4 causes mitochondrial stress, which leads to the leakage of mtDNA and thereby upregulation of type I interferon signaling. This study provides proof-of-principle for the application of iPSC arrays in GWAS and identifies NDUFA4 as a previously unknown susceptibility locus for viral infection.
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