Jean-Paul Armache, assistant professor of biochemistry and molecular biology, has been awarded seed funding from the Huck Institutes of the Life Sciences at Penn State to use cryo-electron microscopy to study how an important SARS-CoV-2 protein binds to and takes over the human ribosome—a protein factory in the cell that the virus uses to copy itself.
“By generating high-resolution images of this protein bound to a human ribosome, we may be able to infer how the protein ultimately takes over the ribosome,” said Armache. “We hope this information will help generate ideas for how to derail this system in this and other coronaviruses.”
Ribosomes assemble proteins based on the genetic blueprint carried by RNA through a process called translation. However, the SARS-CoV-2 virus contains a nonstructural protein called nsp1 that inhibits this process in the cells it infects. Instead, the virus inserts its own RNA, coopting the host ribosome to produce viral proteins in order to make more viruses.
“This protein acts like Cerberus from Greek mythology, refusing to let the dead leave the underworld,” said Armache. “The protein destroys or otherwise prevents human RNA from getting to the ribosome, but allows viral RNA to get through. We are using cryo-electron microscopy to get a better picture of this process. Once we can see how the protein binds to the ribosome, we may be able to infer the mechanism by which this process occurs.”
This protein may also play a role in leading to an overreaction of the human immune system, known as a cytokine storm, that leads to severe illness in many patients with COVID-19.
Armache hopes that understanding how this viral protein interacts with a host’s ribosomes will lead to a way to disrupt the function of the protein, and thus the virus itself. For example, a drug that prevents the protein from binding to the ribosome or that prevents the protein from turning off the production of human proteins would stop the virus from replicating and give the immune system time to clear the infection.
“Other coronaviruses, like MERS and SARS-CoV-1, also use this protein, so this information may also provide tools to prepare for the next coronavirus pandemic,” said Armache.
“I worked in a protein translation lab while I was getting my Ph.D., but I never thought I would return to translation,” said Armache. “This work is very different than my current line of research. But this also shows that science is not actually a preset field. If you have an idea and the power to do so, you should pursue it, because someone else might not have had the idea and it could potentially help others.”
About the Coronavirus Research Seed Fund
On March 3, the Penn State Huck Institutes of the Life Sciences launched a rapid-response, internal call-for-proposals across the University to address the emerging COVID-19 outbreak, with support from the Materials Research Institute, Social Sciences Institute, Institutes for Energy and the Environment, and the Institute for Computational and Data Science.
Over the course of five weeks, units across Penn State stepped up to assist. To date, more than 135 faculty members in 48 research teams from across ten colleges at Penn State have been granted an overall $2.4 million in seed funding to initiate their vitally important work.
The projects span six core areas: Diagnostics and Detection, Therapeutics and Vaccines, Transmission-blocking Interventions, Social Sciences, Cohort Studies, and Predictive Modeling.