What Makes Someone a Likely Target of a Virus?

The Context: Perhaps you’ve noticed that some people seem to get COVID-19 more easily than others. This could be due to differences in our genomes. Our genes can tell us a lot about our susceptibility to disease, and new strategies for studying the genetics of large groups (called ‘Genome Wide Association Studies’, or GWAS) have opened the door for better understanding of the interplay between our DNA and our risk for developing a variety of diseases, including infectious ones such as COVID-19 or Zika. However, it can be expensive and labor intensive to recruit thousands of participants for such large scale research, and it is difficult to study genetic susceptibility to rapidly changing viruses in this way.

The Study: Using stem cells from 100 genetically diverse individuals, researchers were able to create a “GWAS study in a dish” to examine how one’s genetics may impact their risk for contracting viruses such as Zika, COVID-19, or Dengue. The team identified a certain genetic variation in mitochondria (the cell’s energy center) that hinders the body’s ability to fight off infection. The study, led by NYSCF – Robertson Stem Cell Investigator Alumna Shuibing Chen, PhD, of Weill Cornell Medicine in collaboration with NYSCF Research Institute scientists led by Scott Noggle, PhD, appears in Cell Stem Cell.

The Importance: This study provides proof of principle that stem cells can be used as a tool for conducting efficient, large scale research into how our genetics impacts our disease risk. The study also points to a genetic variant that puts individuals at higher risk for contracting viruses – a finding that could inform strategies for preventing or treating the spread of disease.

“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, a professor of chemical biology in surgery and in biochemistry and a member of the Hartman Institute for Organ Regeneration in an article from Weill Cornell.

The team leveraged The NYSCF Global Stem Cell Array®, our robotic system for rapidly creating stem cells from a sample of skin or blood, to make stem cells from 100 genetically diverse donors. 

“Importantly, The Array lets us quickly create high quality stem cells, allowing us to capture the capabilities of a GWAS study, but all in a dish,” remarked Dr. Noggle. “We can use this model to make significant insights at a large scale.”

“[With this approach], we don’t need a million patients to perform a GWAS study,” said Dr. Chen. “We find that even 100 patients’ donor cells were enough to identify genes important for disease susceptibility.”

How One Gene Could Determine Whether You Contract a Virus

Using their new model, the team exposed cells to viruses to see whether certain genetic variations made the cells more susceptible to infection.

The researchers found that a certain genetic variant in a mitochondrial gene called NDUFA4 made cells more likely to be infected with the Zika virus. When this gene was inactivated with CRISPR gene editing, cells weren’t as likely to be infected with Zika, the Dengue virus, or the SARS-CoV-2 virus. By contrast, cells from patients with COVID-19 expressed higher levels of NDUFA4 than cells from healthy donors.

How is NDUFA4 regulating whether someone contracts a virus?

Lead author Yuling Han, PhD, a postdoctoral associate in surgery at Weill Cornell Medicine, discovered that when expression of the NDUFA4 gene is reduced, a cell’s mitochondria leaks certain proteins into the body of a cell, triggering an immune response that fights off infection. 

“The cells release interferon, which inhibits many types of viruses from growing in a cell,” Dr. Han explained.

If the gene is more active, this process doesn’t happen (meaning: probable infection). Knowing this opens the door for new strategies to prevent or treat disease.

“We think we will find new treatment targets for infectious diseases,” remarked Dr. Han.

Next, Dr. Chen plans to use the model to identify genes that contribute to 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.”

Cover image: ZIKA virus-infected brain organoids. Colors indicate Zika virus (blue), neuronal stem cells (red) and neuronal cells (green). Image courtesy of the Chen lab.

Journal Article:

A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants
Yuling Han, Lei Tan, Ting Zhou, Liuliu Yang, Lucia Carrau, Lauretta A. Lacko, Mohsan Saeed, Jiajun Zhu, Zeping Zhao, Benjamin E. Nilsson-Payant, Filipe Tenorio Lira Neto, Clare Cahir, Alice Maria Giani, Jin Chou Chai, Yang Li, Xue Dong, Dorota Moroziewicz, The NYSCF Global Stem Cell Array Team, Daniel Paull, Tuo Zhang, Soyeon Koo, Christina Tan, Ron Danziger, Qian Ba, Lingling Feng, Zhengming Chen, Aaron Zhong, Gilbert J. Wise, Jenny Z. Xiang, Hui Wang, Robert E. Schwartz, Benjamin R. tenOever, Scott A. Noggle, Charles M. Rice, Qibin Qi, Todd Evans, Shuibing Chen. Cell Stem Cell. 2022. DOI: https://doi.org/10.1016/j.stem.2022.09.008