Photo: Chen Lab
A mitochondrial gene plays a crucial role in genetic susceptibility to Zika, Dengue, and SARS-CoV-2 infections, a study by Weill Cornell Medicine investigators showed.
The study, published Oct. 6 in Cell Stem Cell, provides proof of the principle that cell-based genome-wide association studies (GWAS) could be a valuable tool for studying genetic susceptibility to infections and other diseases. Genome-wide association studies scan the genomes of hundreds or thousands of people looking for genetic changes associated with diseases. Dr. Shuibing Chen, the Kilts Family Professor of Surgery and Director of the Diabetes Program in the Department of Surgery at Weill Cornell Medicine, and her colleagues built a laboratory platform that is essentially a GWAS study in a dish. Instead of enrolling people, they used cells donated by patients that were coaxed back into a stem-cell-like or early developmental state that can grow into any other type of tissue with the appropriate growth factor. Then, they used the platform to screen for genes that increase the likelihood of infection with the Zika virus.
“We show that induced pluripotent stem cells are a very powerful model to study how genetic differences contribute to susceptibility to diseases, including COVID-19,” said Dr. Chen, the study’s senior author.
Over the past decade and a half, GWAS studies have emerged as a powerful tool to study genetic risk factors for disease, Dr. Chen said. But teasing apart the contributions of genes and environmental factors is difficult. To overcome this challenge, scientists have increased the size of their studies from about 1,000 patients to studies enrolling millions or more to have adequate statistical power.
“It’s very expensive and labor intensive,” said Dr. Chen, who is also a professor of chemical biology in surgery and in biochemistry and a member of the Hartman Institute for Organ Regeneration at Weill Cornell Medicine.
It’s also challenging to study genetic susceptibility to rapidly changing viruses like SARS-CoV-2 this way, she said. Dr. Chen and her colleagues used their stem-cell-based GWAS study model to look for disease susceptibility genes in patient stem cells grown in identical environmental conditions in Petri dishes.
“We don’t need a million patients to perform a GWAS study,” she said. “We find that even 100 patients’ donor cells were enough to identify genes important for disease susceptibility.”
Study co-author Dr. Ting Zhou, a former postdoctoral associate in Dr. Chen’s lab and now director of the stem cell research facility at Memorial Sloan Kettering Cancer Center, used the platform to screen 100 patients’ stem cells for genetic variations. She found that cells with genetic variations affecting a mitochondrial gene called NDUFA4 were more likely to be infected with the Zika virus. Lead author Dr. Yuling Han, a postdoctoral associate in surgery at Weill Cornell Medicine, used CRISPR gene-editing technology to remove the NDUFA4 gene in the cells. He found that the cells lacking this gene are less susceptible to infection with Zika, the Dengue virus, and the SARS-CoV-2 virus. By contrast, cells from patients with COVID-19 expressed higher levels of NDUFA4 than cells from healthy donors.
Dr. Han conducted studies to discover why. He showed that the loss or reduced expression of the NDUFA4 gene stresses the mitochondria and causes mitochondrial proteins to leak into the cell’s cytoplasm and triggers an innate immune response usually reserved to fight infection.
“The cells release interferon, which inhibits many types of viruses from growing in a cell,” Dr. Han explained.
“We think we will find new treatment targets for infectious diseases,” he said.
Dr. Chen is currently using the platform to search for genes involved in type 1 and type 2 diabetes.
“We think this model can be used to study many kinds of diseases,” she said. “We hope we can encourage other scientists to use this platform to study the genetic basis of disease more efficiently and find potential new treatments.”