Study identifies mechanism that enables SARS viruses to efficiently replicate in infected cells

Coronavirus researchers have now identified how SARS viruses improve the production of viral proteins in infected cells such that several new copies of the virus can be produced.

Image Credit: © Alissa Eckert, MSMI, Dan Higgins, MAMS.

The study was headed by Professor Rolf Hilgenfeld from the University of Lübeck and PD Dr Albrecht von Brunn from Ludwig-Maximilians-Universität München.

Specifically, apart from SARS-CoV and SARS-CoV-2, other coronaviruses do not employ this mechanism, which may thus offer a potential explanation for the considerably higher pathogenicity of the SARS viruses. The study results were reported in The EMBO Journal.

Over five decades ago, scientists discovered coronaviruses that cause harmless colds in humans. When the SARS coronavirus emerged in 2002/2003, it was the first one identified to cause severe pneumonia in infected people.

By comparing the RNA genomes of innocuous coronaviruses with those of the SARS coronavirus, researchers were able to find a region that occurred only in the latter, known as the “SARS-unique domain” (SUD). Genomic regions such as this and their protein products may be associated with the remarkable pathogenicity of SARS coronavirus and its cousin, the COVID-19 virus SARS-CoV-2.

The research teams headed by Hilgenfeld and von Brunn revealed that the SUD proteins of both the viruses interact with Paip-1, a human protein that takes part in the first steps of protein synthesis.

Along with Paip-1 and other proteins found in human cells, SUD seems to bind with the ribosomes, the molecular machines that cause protein synthesis in cells. This would result in an improvement in the production of all proteins, both those of the virus and those of the host cell.

But the messenger RNA molecules in cells infected with SARS-CoV or SARS-CoV-2 code for host proteins and are selectively destroyed by Nsp1, a viral protein. Due to this complex process, the infected cell largely generates viral proteins, thus enabling several new copies of the virus to be created.

The research team led by Albrecht von Brunn identified the interaction between the proteins Paip-1 and SUD many years ago.

Being an experienced coronavirologist, I knew that one has to inspect the special regions of the SARS genome when trying to understand this virus.”

Albrecht von Brunn, Ludwig-Maximilians-Universität München

The breakthrough achieved by the Munich scientists was of great interest to Hilgenfeld, whose research team had already unraveled the three-dimensional structure of the SUD protein a few years ago.

Both the research teams collaborated. While a group leader at Sichuan University in Chengdu (China), Dr. Jian Lei from Hilgenfeld’s team successfully crystallized the complex formed by Paip-1 and SUD while also identifying its three-dimensional structure using X-ray crystallography.

Dr. Yue “Lizzy” Ma-Lauer, co-first author of the study from von Brunn’s team characterized the complexity of both the proteins and their function with the help of a range of cell-biological and biophysical methods.