New Insights into How SARS-CoV-2 Shuts Off the ‘Alarm System’ in Human Cells

The Context: Scientists now understand the symptoms of COVID-19 fairly well, but there are still many unknowns about what happens to cells that are infected by the SARS-CoV-2 virus, which, if answered, could help us learn how to better fight the virus. 

The Study: Infection with the SARS-CoV-2 virus suppresses several critical defense functions used by human cells to fight off viruses, effectively disabling the cell’s ‘alarm system,’ finds a new study in Cell by NYSCF – Robertson Stem Cell Investigator Mitch Guttman, PhD, of the California Institute of Technology.

The Importance: This study sheds light on several specific ways that the SARS-CoV-2 virus disrupts the function of human cells, providing a framework for studying emerging viruses and clues for therapeutic efforts.

“Viruses are amazing,” said Emily Bruce, PhD, faculty scientist at the University of Vermont and a co-first author on the paper, in an article from CalTech. “Viruses and host cells are continually in an evolutionary arms race to outwit one another. SARS-CoV-2 has evolved intricate and specific ways to disable cells without killing them outright, so that the virus can still use the cell for its own purposes.”

How SARS-CoV-2 Outwits Our Cells

Dr. Guttman’s team, armed with an array of molecular tools, set out to investigate how the viral proteins produced by SARS-CoV-2 interact with the molecules in human cells in a lab dish, so as to identify how this new virus overcomes cellular defense mechanisms.

Normally, when a human cell is infected by a virus, it sets off a defense process to shut down the infection. This defense process relies heavily on the production and release of proteins called interferons, which signal nearby cells about the infection. Importantly, patients with severe COVID-19 seem to have lower levels of interferons, indicating that these molecules are critical for effectively fighting off the virus.  

So how does SARS-CoV-2 infection get past cellular defenses? Dr. Guttman’s team investigated how the viral proteins interact with human cellular RNA molecules, and examined every step of the interferon response, from the splicing of mRNA molecules created from human DNA, to the translation of those mRNA molecules into proteins, to the trafficking of these proteins outside of the cell. 

Surprisingly, they found that SARS-CoV-2 interferes with this process at virtually every stage: it can prevent mRNA from being spliced, block a ribosome from forming new proteins, and prevent proteins from being trafficked outside the cell, altogether disabling a cell’s ‘alarm system.’

“Each of the processes that SARS-CoV-2 disrupts — splicing, translation, and protein trafficking — is so important for converting the human genetic material into proteins, and they are essential for human biology,” noted Dr. Guttman. “In fact, discovery of each of these processes has separately led to the awarding of a Nobel Prize. These are machines that are central to life. We cannot exist without them. SARS-CoV-2 has evolved in very specific ways to disable these cellular machines and disrupt their functions.”

Interestingly, the viral protein that interferes with ribosome function is called NSP1, and while it blocks human mRNA from entering a ribosome, it allows viral mRNA to waltz right in. It is able to do this because it possesses a genetic signature that acts as a key, letting it into a ribosome. The scientists believe that attacking this ‘key’ could be a possible approach for antiviral therapeutics.

Looking to the Future

Dr. Guttman’s team is optimistic that a better understanding of SARS-CoV-2’s behaviors will help scientists develop new treatments, and that methods employed in this work could be important for future virus research.

“Our study illustrates the importance of basic science research and establishes a pipeline to address newly emerging RNA viruses in the future,” says co-first author Abhik Banerjee, a graduate student in the Guttman laboratory. 

“Our ability to interrogate the human RNA targets of SARS-CoV-2 proteins allowed us to identify these mechanisms without prior evidence,” agrees Mario Blanco, PhD, a research scientist in Dr. Guttman’s lab. “The methods and practices we developed here will allow us to apply these same processes to emergent diseases and even currently existing viruses where we lack a deep understanding of mechanism.”

Journal Article: 

SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses
Abhik K. Banerjee, Mario R. Blanco, Emily A. Bruce, Drew D. Honson, Linlin M. Chen, Amy Chow, Prashant Bhat, Noah Ollikainen, Sofia A. Quinodoz, Colin Loney, Jasmine Thai, Zachary, D. Miller, Aaron E. Lin, Madaline M. Schmidt, Douglas G. Stewart, Daniel Goldfarb, Giuditta De Lorenzo, Suzannah J. Rihn, Rebecca Voorhees, Jason W. Botten, Devdoot Majumdar, Mitchell Guttman. Cell. 2020. DOI: https://doi.org/10.1016/j.cell.2020.10.004

Photo credit: Guttman lab, CalTech