Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.

Identification of SARS-CoV-2 inhibitors using lung and colonic organoids.

There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes1. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.

Research on ultrawideband photodetector module based on parasitic parameter regulation.

A four-channel ultrawideband photodetector (PD) module with a size of 26.1 mm ×33.2 mm × 8.5 mm has been demonstrated in our laboratory. We propose a method to improve the bandwidth of the PD module based on compensating parasitic parameters by dual resistance regulation on the P and N terminals of the PD chip. A small signal equivalent circuit model with package matching network is established for the PD module, and the effectiveness of the proposed method and the accuracy of the model are verified by experiments. A four-channel photodetector module with a -3 dB bandwidth of up to 67 GHz is fabricated by using photodetector chips with -3 dB bandwidths of 46 GHz, and the responsivity is up to 0.50A/W.

Broadband photoelectric fusion transceiver-multiplexed conversion system with high spurious rejection.

In this paper, a broadband photoelectric fusion transceiver-multiplexed system is proposed to realize a frequency converter. The system achieves a high spurious suppression ratio through two frequency conversions that utilize the advantages of microwave and photonics technology simultaneously to reduce the complexity of the system and improve the effective spectrum utilization. In addition, the core components, such as the Mach-Zehnder modulator (MZM), are multiplexed in the up and down frequency conversion link. High-frequency local oscillator (LO) signals are used to keep image frequency signals and various kinds of spurious signals obtained by beating frequency outside the system bandwidth. Experimental results demonstrate that the operating frequency ranges from 2 to 18 GHz with high performance for both transmitter and receiver. The image rejection is 57.35 dB for up-conversion and 46.56 dB for down-conversion, and the in-band spurious suppression achieves at least 55.02 dB. At the same time, the spurious-free dynamic range (SFDR) can reach at least 89.11d B⋅H z 2/3.

Simple microwave photonic downconversion channelizer based on multi-wavelength laser sources.

This work presents a simple microwave photonic downconversion channelizer based on multi-wavelength laser sources. The design of two laser diode (LD) arrays enables signal multiplexing and simultaneous multichannel downconversion processing, which provide stable, relatively flat, and strong multi-frequency combs. A proof-of-concept experiment was taken, showing that 14.375-17.75 GHz broadband radio frequency (RF) signals were successfully downconverted to the same intermediate frequency (IF) and were sliced into four subchannels with 875 MHz bandwidth showing excellent image rejection and channel uniformity, which agrees with the simulation results. The spurious free dynamic range (SFDR) of the proposed RF channelizer is 100dBHz2/3, the image rejection is over 28 dB, and the frequency measurement error is less than ±6MHz. Replacing optical filters with electrical filters, the proposed simple optoelectronic hybrid reconfigurable microwave photonic channelizer system acquits stable performance and high maturity and meets the application requirements, behaving with stupendous potential in fields such as radar, satellite communication, electronic warfare, and others.

Ultra-wideband tunable metamaterial perfect absorber based on vanadium dioxide.

A dynamically adjustable ultra-wideband metamaterial perfect absorber (MPA) is proposed which consists of three resonance rings based on vanadium dioxide (VO2) and a metal ground layer separated by a dielectric spacer. The simulation results show that the terahertz (THz) absorption bandwidth of more than 90% absorptance reaches 3.30 THz, which covers from 2.34 to 5.64 THz, under different incident polarization angles. The range is better than that of previous VO2-based reports. Moreover, when the conductivity of VO2 changes from 200 S/m to 2×105 S/m, the absorption peak intensity can be adjusted continuously from 4% to 100%. The key is to optimize the geometric structure through interference cancellation and impedance matching theory, to achieve better absorption bandwidth and efficiency. Besides, the terahertz absorber has a wide-angle absorption effect both in TE and TM waves. Thus, the designed absorber may have many potential applications in modulating, sensing and imaging technology.

Photo-assisted self-interference cancellation for in-band full-duplex radio-over-fiber system.

An optical approach to cancel the radio frequency self-interference for an in-band full-duplex radio-over-fiber system is proposed and experimentally demonstrated based on two Mach-Zehnder modulators and a balanced photodetector (BPD). The cancellation depth is larger than 50 dB and 24 dB for the single frequency and for a wideband signal, respectively. The application of the BPD eliminates the common mode noise and reduces no system flexibility because signal transmission is in one optical fiber by polarization multiplexing technology, instead of two fibers in the traditional self-interference cancellation system with a BPD. In addition, with no electrical delay and attenuation applied, the operational frequency band and cancellation depth are not confined by electronic devices.

High Dietary Fat and Selenium Concentrations Exert Tissue- and Glutathione Peroxidase 1-Dependent Impacts on Lipid Metabolism of Young-Adult Mice.

BACKGROUND: Excessive dietary selenium (Se; 3 mg/kg) or fat (>25%) intakes and overproduction of glutathione peroxidase 1 (GPX1) adversely affect body lipid metabolism. OBJECTIVE: The objective was to reveal impacts and mechanisms of a moderately high Se and a high fat intake on lipid metabolism in Gpx1 knockout (KO) and wild-type (WT) mice. METHODS: The KO and WT mice (males, 12-wk-old, body weight = 24.8 ± 0.703 g) were allotted to 4 groups each (n = 5) and fed a sucrose-torula yeast basal diet (5% corn oil) supplemented with 0.3 or 1.0 mg (+Se) Se/kg (as sodium selenite) and 0% or 25% [high-fat (HF)] lard for 6 wk. Multiple physiological and molecular biomarkers (68) related to lipid metabolism and selenogenome expression in plasma, liver, and/or adipose tissue were analyzed by 2-way (+Se by HF) ANOVA. RESULTS: Compared with the control diet, the +Se diet decreased (P < 0.05) body-weight gain and plasma and liver concentrations of lipids (22-66%) but elevated (≤1.5-fold, P < 0.05) adipose tissue concentrations of lipids in the WT mice. The +Se diet up- and downregulated (P < 0.05) mRNA and/or protein concentrations of factors related to lipogenesis, selenogenome, and transcription, stress, and cell cycle in the liver (26% to 176-fold) and adipose tissues (14% to 1-fold), respectively, compared with the control diet in the WT mice. Many of these +Se diet effects were different (P < 0.05) from those of the HF diet and were eliminated or altered (P < 0.05) by the KO. CONCLUSIONS: The +Se and HF diets exerted tissue-specific and GPX1 expression-dependent impacts on lipid metabolism and related gene expression in the young-adult mice. Our findings will help reveal metabolic potential and underlying mechanisms of supplementing moderately high Se to subjects with HF intakes.

12.5 Gb/s multi-channel broadcasting transmission for free-space optical communication based on the optical frequency comb module.

A wide-spectrum, ultra-stable optical frequency comb (OFC) module with 100 GHz frequency intervals based on a quantum dot mode locked (QDML) laser is fabricated by our lab, and a scheme with 12.5 Gb/s multi-channel broadcasting transmission for free-space optical (FSO) communication is proposed based on the OFC module. The output power of the OFC is very stable, with the specially designed circuit and the flatness of the frequency comb over the span of 6 nm, which can be limited to 1.5 dB. Four channel wavelengths are chosen to demonstrate one-to-many channels for FSO communication, like optical wireless broadcast. The outdoor experiment is established to test the bit error rate (BER) and eye diagrams with 12.5 Gb/s on-off keying (OOK). The indoor experiment is used to test the highest traffic rate, which is up to 21 Gb/s for one-hop FSO communication. To the best of our knowledge, this scheme is the first to propose the realization of one-to-many broadcasting transmission for FSO communication based on the OFC module. The advantages of integration, miniaturization, channelization, low power consumption, and unlimited bandwidth of one-to-many broadcasting communication scheme, shows promising results on constructing the future space-air-ground-ocean (SAGO) FSO communication networks.

High Dietary Selenium Intake Alters Lipid Metabolism and Protein Synthesis in Liver and Muscle of Pigs.

BACKGROUND: Prolonged high intakes of dietary selenium have been shown to induce gestational diabetes in rats and hyperinsulinemia in pigs. OBJECTIVE: Two experiments were conducted to explore metabolic and molecular mechanisms for the diabetogenic potential of high dietary selenium intakes in pigs. METHODS: In Expt. 1, 16 Yorkshire-Landrace-Hampshire crossbred pigs (3 wk old, body weight = 7.5 ± 0.81 kg, 50% males and 50% females) were fed a corn-soybean meal basal diet supplemented with 0.3 or 1.0 mg Se/kg (as selenium-enriched yeast for 6 wk). In Expt. 2, 12 pigs of the same crossbreed (6 wk old, body weight = 16.0 ± 1.8 kg) were fed a similar basal diet supplemented with 0.3 or 3.0 mg Se/kg for 11 wk. Biochemical and gene and protein expression profiles of lipid and protein metabolism and selenoproteins in plasma, liver, muscle, and adipose tissues were analyzed. RESULTS: In Expt. 1, the 1-mg-Se/kg diet did not affect body weight or plasma concentrations of glucose and nonesterified fatty acids. In Expt. 2, the 3-mg-Se/kg diet, compared with the 0.3-mg-Se/kg diet, increased (P < 0.05) concentrations of plasma insulin (0.2 compared with 0.4 ng/mL), liver and adipose lipids (41% to 2.4-fold), and liver and muscle protein (10-14%). In liver, the 3-mg-Se/kg diet upregulated (P < 0.05) the expression, activity, or both of key factors related to gluconeogenesis [phosphoenolpyruvate carboxykinase (PEPCK); 13%], lipogenesis [sterol regulatory element binding protein 1 (SREBP1), acetyl-coenzyme A carboxylase (ACC), and fatty acid synthase (FASN); 46-90%], protein synthesis [insulin receptor (INSR), P70 ribosomal protein S6 kinase (P70), and phosphorylated ribosomal protein S6 (P-S6); 88-105%], energy metabolism [AMP-activated protein kinase (AMPK); up to 2.8-fold], and selenoprotein glutathione peroxidase 3 (GPX3; 1.4-fold) and suppressed (P < 0.05) mRNA levels of lipolysis gene cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1; 88%) and selenoprotein gene selenoprotein W1 (SEPW1; 46%). In muscle, the 3-mg-Se/kg diet exerted no effect on the lipid profiles but enhanced (P < 0.05) expression of P-S6 and mammalian target of rapamycin (mTOR; 42-176%; protein synthesis); selenoprotein P (SELP; 40-fold); and tumor suppressor protein 53 (P53) and peroxisome proliferator-activated receptor γ (PPARG; 52-58%; lipogenesis) and suppressed (P < 0.05) expression of INSR (59%; insulin signaling); selenoprotein S (SELS); deiodinases, iodothyronine, type I (DIO1); and thioredoxin reductase 1 (TXNRD1; 50%; selenoproteins); and ACC1 and FASN (35-51%; lipogenesis). CONCLUSION: Our research showed novel roles, to our best knowledge, and mechanisms of high selenium intakes in regulating the metabolism of protein, along with that of lipid, in a tissue-specific fashion in pigs.

Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons.

The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months to years for reaching adult-like function. Prolonged in vitro maturation presents a major challenge to stem cell-based applications in modeling and treating neurological disease. Therefore, we designed a high-content imaging assay based on morphological and functional readouts in hPSC-derived cortical neurons which identified multiple compounds that drive neuronal maturation including inhibitors of lysine-specific demethylase 1 and disruptor of telomerase-like 1 and activators of calcium-dependent transcription. A cocktail of four factors, GSK2879552, EPZ-5676, N-methyl-D-aspartate and Bay K 8644, collectively termed GENtoniK, triggered maturation across all parameters tested, including synaptic density, electrophysiology and transcriptomics. Maturation effects were further validated in cortical organoids, spinal motoneurons and non-neural lineages including melanocytes and pancreatic ß-cells. The effects on maturation observed across a broad range of hPSC-derived cell types indicate that some of the mechanisms controlling the timing of human maturation might be shared across lineages.

Nutrient Composition of Ovary, Hepatopancreas and Muscle Tissues in Relation to Ovarian Development Stage of Female Swimming Crab, Portunus trituberculatus.

The swimming crab Portunus trituberculatus is one of the most important economic species in China and its mature ovary often determines its commercial value and production. Although the ovary maturation of crustaceans is generally affected by exogenous nutrition, the specific nutritional needs of ovary maturation of P. trituberculatus are poorly understood. To this end, we collected the P. trituberculatus samples with five ovarian maturation stages and measured their biochemical composition of the ovary, hepatopancreas, and muscle at each ovarian developmental stage. We further analyzed their relation to the ovarian developmental stage of P. trituberculatus by principal components analysis (PCA). We found the levels of branched-chain amino acids, long-chain polyunsaturated fatty acids (LC-PUFA), and monounsaturated fatty acids (MUFAs) in the ovary and hepatopancreas increased during the ovary maturation process, and also passively correlated with ovarian developmental stage, which highlights the necessity of these specific nutrients for oogenesis and for improving the nutrient quality of crabs. In addition, we found an increasing tendency of carotenoid content and phosphatidylcholine in phospholipid in the ovary from the pre-developmental stage to the proliferative stage, but not in the hepatopancreas and muscle, which highlights the possible involvement of carotenoids during the rapid oocyte development process. Our study may provide valuable information for developing a suitable broodstock diet that promotes the ovarian maturation of adult P. trituberculatus and ensures high-quality larval production.

SXRF for Studying the Distribution of Trace Metals in the Pancreas and Liver.

Transition metals such as iron, copper and zinc are required for the normal functioning of biological tissues, whereas others, such as cadmium, are potentially highly toxic. Any disturbances in homeostasis caused by lack of micronutrients in the diet, pollution or genetic heredity result in malfunction and/or diseases. Here, we used synchrotron X-ray fluorescence, SXRF, microscopy and mice with altered functions of major antioxidant enzymes to show that SXRF may become a powerful tool to study biologically relevant metal balance in the pancreas and liver of mice models with disturbed glucose homeostasis.

Interdependencies of Gene Expression and Function between Two Redox Enzymes and REG Family Proteins in Murine Pancreatic Islets and Human Pancreatic Cells.

Our laboratory previously revealed that regenerating islets-derived protein 2 (REG2) was diminished in pancreatic islets of glutathione peroxidase-1-overexpressing mice (Gpx1-OE). It remained unknown if there is an inverse relationship between the expression and function of all Reg family genes and antioxidant enzymes in the pancreatic islets or human pancreatic cells. This research was to determine how altering the Gpx1 and superoxide dismutase-1 (Sod1) genes alone or together (dKO) affected the expression of all seven murine Reg genes in murine pancreatic islets. In Experiment 1, Gpx1-/-, Gpx1-OE, their wild-type (WT), Sod1-/-, dKO, and their WT (male, 8-wk old, n = 4-6) were fed a Se-adequate diet and their islets were collected to assay the mRNA levels of Reg family genes. In Experiment 2, islets from the six groups of mice were treated with phosphate-buffered saline (PBS), REG2, or REG2 mutant protein (1 µg/mL), and/or GPX mimic (ebselen, 50 µM) and SOD mimic (copper [II] diisopropyl salicylate, CuDIPS, 10 µM) for 48 h before the proliferation assay using bromodeoxyuridine (BrdU). In Experiment 3, human pancreatic cells (PANC1) were treated with REG2 (1 µg/mL) and assayed for REG gene expression, GPX1 and SOD1 activities, viability, and responses to Ca2+. Compared with the WT, knockouts of Gpx1 and/or Sod1 up-regulated (p < 0.05) the mRNA levels of most of the murine Reg genes in islets whereas the Gpx1 overexpression down-regulated (p < 0.05) Reg mRNA levels. REG2, but not the REG2 mutant, inhibited islet proliferation in Gpx1 or Sod1-altered mice. Such inhibition was abolished by co-incubation the Gpx1-/- islets with ebselen and the Sod1-/- islets with CuDIPS. Treating PANC1 cells with murine REG2 protein induced expression of its human orthologue REG1B and three other REG genes, but decreased SOD1 and GPX1 activities and cell viability. In conclusion, our results revealed an interdependence of REG family gene expression and/or function on intracellular GPX1 and SOD1 activities in murine islets and human pancreatic cells.

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

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.

An integrative single-cell multi-omics profiling of human pancreatic islets identifies T1D associated genes and regulatory signals.

Genome wide association studies (GWAS) have identified over 100 signals associated with type 1 diabetes (T1D). However, translating any given T1D GWAS signal into mechanistic insights, including putative causal variants and the context (cell type and cell state) in which they function, has been limited. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in healthy and autoantibody+ (AAB+) human islets, as well as islets under multiple T1D stimulatory conditions. We broadly nominate effector cell types for all T1D GWAS signals. We further nominated higher-resolution contexts, including effector cell types, regulatory elements, and genes for three independent T1D risk variants acting through islet cells within the pancreas at the DLK1/MEG3, RASGRP1, and TOX loci. Subsequently, we created isogenic gene knockouts DLK1-/-, RASGRP1-/-, and TOX-/-, and the corresponding regulatory region knockout, RASGRP1Δ, and DLK1Δ hESCs. Loss of RASGRP1 or DLK1, as well as knockout of the regulatory region of RASGRP1 or DLK1, increased ß cell apoptosis. Additionally, pancreatic ß cells derived from isogenic hESCs carrying the risk allele of rs3783355A/A exhibited increased ß cell death. Finally, RNA-seq and ATAC-seq identified five genes upregulated in both RASGRP1-/- and DLK1-/- ß-like cells, four of which are associated with T1D. Together, this work reports an integrative approach for combining single cell multi-omics, GWAS, and isogenic hESC-derived ß-like cells to prioritize the T1D associated signals and their underlying context-specific cell types, genes, SNPs, and regulatory elements, to illuminate biological functions and molecular mechanisms.

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes, including shared transcriptomic signatures, autophagic body accumulation, and impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.

Role and mechanism of REG2 depletion in insulin secretion augmented by glutathione peroxidase-1 overproduction.

We previously reported a depletion of murine regenerating islet-derived protein 2 (REG2) in pancreatic islets of glutathione peroxidase-1 (Gpx1) overexpressing (OE) mice. The present study was to explore if and how the REG2 depletion contributed to an augmented glucose stimulated insulin secretion (GSIS) in OE islets. After we verified a consistent depletion (90%, p < 0.05) of REG2 mRNA, transcript, and protein in OE islets compared with wild-type (WT) controls, we treated cultured and perifused OE islets (70 islets/sample) with REG2 (1 µg/ml or ml · min) and observed 30-40% (p < 0.05) inhibitions of GSIS by REG2. Subsequently, we obtained evidences of co-immunoprecipitation, cell surface ligand binding, and co-immunofluorescence for a ligand-receptor binding between REG2 and transmembrane, L-type voltage-dependent Ca2+ channel (CaV1.2) in beta TC3 cells. Mutating the C-type lectin binding domain of REG2 or deglycosylating CaV1.2 removed the inhibition of REG2 on GSIS and(or) the putative binding between the two proteins. Treating cultured OE and perifused WT islets with REG2 (1 µg/ml or ml · min) decreased (p < 0.05) Ca2+ influx triggered by glucose or KCl. An intraperitoneal (ip) injection of REG2 (2 µg/g) to OE mice (6-month old, n = 10) decreased their plasma insulin concentration (46%, p < 0.05) and elevated their plasma glucose concentration (25%, p < 0.05) over a 60 min period after glucose challenge (ip, 1 g/kg). In conclusion, our study identifies REG2 as a novel regulator of Ca2+ influx and insulin secretion, and reveals a new cascade of GPX1/REG2/CaV1.2 to explain how REG2 depletion in OE islets could decrease its binding to CaV1.2, resulting in uninhibited Ca2+ influx and augmented GSIS. These findings create new links to bridge redox biology, tissue regeneration, and insulin secretion.

A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.

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 strategy 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 associated 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.