Weizmann Institute Scientists Reveal the Triple Threat of Coronavirus

Severe symptoms of COVID-19, leading often to death, are thought to result from the patient’s own acute immune response rather than from damage inflicted directly by the virus. Intensive research efforts are therefore seeking to determine how the SARS-CoV-2 virus manages to mount an effective invasion while throwing the immune system off course. A new study, published in Nature, reveals a multipronged strategy that the virus employs to ensure its quick and efficient replication, while avoiding detection by the immune system. The study, conducted jointly by the research groups of Dr. Noam Stern-Ginossar at the Weizmann Institute of Science and Dr. Nir Paran and Dr. Tomer Israely of the Israel Institute for Biological, Chemical and Environmental Sciences, focused on understanding the molecular mechanisms at work during infection by SARS-CoV-2 at the cellular level.

During an infection, our cells are normally able to recognize that they’re being invaded and quickly dispatch signaling molecules, which alert the immune system of the attack. With SARS-CoV-2, it was apparent early on that something was not working quite right – not only is the immune response delayed, enabling the virus to quickly replicate, unhindered, but once this response does occur it’s often so severe that instead of fighting the virus it causes damage to its human host. 

“Most of the research that has addressed this issue so far concentrated on specific viral proteins and characterized their functions. Yet not enough is known today about what is actually going on in the infected cells themselves,” says Dr. Stern-Ginossar, who is in Weizmann’s Department of Molecular Genetics. “So we infected cells with the virus and proceeded to assess how infection affects important biochemical processes in the cell, such as gene expression and protein synthesis.”  

When cells are infected by viruses, they start expressing a series of specific antiviral genes – some act as first-line defenders and meet the virus head on in the cell itself, while others are secreted to the cell’s environment, alerting neighboring cells and recruiting the immune system to combat the invader. At this point, both the cell and the virus race to the ribosomes, the cell’s protein synthesis factories, which the virus itself lacks. What ensues is a battle between the two over this precious resource.

The new study has elucidated how SARS-CoV-2 gains the upper hand in this fight: In a matter of hours, it is able to quickly take over the cell’s protein-making machinery and, at the same time, neutralize the cell’s anti-viral signaling, both internal and external, thus delaying and muddling the immune response.

The researchers showed that the virus is able to hack the cell’s hardware, taking over its protein-synthesis machinery, by relying on three separate, yet complementary, tactics. The first is to reduce the cell’s capacity for translating genes into proteins, meaning that fewer proteins are synthesized overall. The second tactic the virus uses is to actively degrade the cell’s messenger RNAs (mRNAs) – the molecules that carry instructions for making proteins from the DNA to the ribosomes – while its own mRNA transcripts remain protected. Finally, the study revealed, the virus is also able to prevent the export of mRNAs from the cell’s nucleus, where they are synthesized, to the cell’s main chamber, where they normally serve as the template for protein synthesis.

“By employing this three-way strategy, which appears to be unique to SARS-CoV-2, the virus is able to efficiently execute what we call ‘host shutoff’ – where the virus takes over the cell’s protein-synthesis capacity,” Dr. Stern-Ginossar explains. “In this way, messages from important anti-viral genes, which the cell rushes to produce upon infection, do not make it to the factory floor to be translated into active proteins, resulting in the delayed immune response we are seeing in the clinic.”

The good news is that the scientists were also successful in identifying the viral proteins involved in the process of host shutoff by SARS-CoV-2, which could spell new opportunities for developing effective COVID-19 treatments.

Study authors also included Yaara Finkel, Avi Gluck, Aharon Nachshon, Dr. Roni Winkler, Tal Fisher, Batsheva Rozman, Dr. Orel Mizrahi, and Dr. Michal Schwartz, all members of Dr. Stern-Ginossar’s group; Dr. Yoav Lubelsky and Binyamin Zuckerman from Prof. Igor Ulitsky’s group in Weizmann’s Department of Biological Regulation; Dr. Boris Slobodin from Weizmann’s Department of Biomolecular Sciences; and Dr. Yfat Yahalom-Ronen and Dr. Hadas Tamir from the Israel Institute for Biological, Chemical and Environmental Sciences.

Dr. Noam Stern-Ginossar’s research is supported by Skirball Chair for New Scientists; the Knell Family Center for Microbiology; the American Committee for the Weizmann Institute of Science 70^th Anniversary Lab; the Ben B. and Joyce E. Eisenberg Foundation; the Maurice and Vivienne Wohl Biology Endowment; and Miel de Botton.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. The Institute’s 3,800-strong scientific community engages in research addressing crucial problems in medicine and health, energy, technology, agriculture, and the environment. Outstanding young scientists from around the world pursue advanced degrees at the Weizmann Institute’s Feinberg Graduate School. The discoveries and theories of Weizmann Institute scientists have had a major impact on the wider scientific community, as well as on the quality of life of millions of people worldwide.