Learn how SARS-CoV-2 highjacks host cell machineries will help develop therapeutic strategies.
As the global coronavirus pandemic continues, scientists are not only trying to find vaccines and drugs to combat it, but also to continually learn more about the virus itself. “We can now expect the coronavirus to become seasonal,” explains Ralf Bartenschlager, a professor in the Department of Infectious Diseases, Molecular Virology, at the University of Heidelberg. “Therefore, prophylactic and therapeutic strategies against this virus need to be developed and implemented urgently.” In a new study, Bartenschlager, with the help of the Schwab team at EMBL Heidelberg and using the EMBL Electron Microscopy Core Facility, performed a detailed imaging analysis to determine how the virus reprogram infected cells.
SARS-CoV-2-infected cells die quite quickly, within just 24 to 48 hours. This shows that the virus damages the human cell in such a way that it is rewired and forced to produce essentially viral offspring. The main aim of the project was therefore to identify the morphological changes in a cell inherent in this reprogramming. “The development of drugs that prevent the viral replication and thus the result of infection, as well as the cell death caused by virus, is key to a better understanding of the biological mechanisms that drive the cycle of replication virus, ”Bartenschlager explained. The team used the imaging facilities at EMBL and state-of-the-art imaging techniques to determine the 3D architecture of cells infected with SARS-CoV-2, as well as changes to cellular architecture caused by the virus.
The team was able to create 3D reconstructions of whole cells and their subcellular compartments. “We provide critical insights into virus-induced structural changes in the human cells studied,” explains Ralf Bartenschlager. The images revealed a marked and massive change in the endomembrane systems of the infected cells – a system that enables the cell to define different compartments and sites. The virus induces membrane changes in such a way that it can produce its own duplicated organs. These are small duplication sections where the viral genome is massively amplified. To do this, the virus needs membrane surfaces. These are created by exploiting a cellular membrane system and creating an organelle, which has a very unique appearance. The scientists describe it as a massive build-up of bubbles: two membrane layers forming a large balloon. Within these balloons – which form a highly shaded section – the viral genomes are multiplied and released to become incorporated into new virus particles.
This striking change in the cells can only be seen a few hours after infection. “We saw how and where the virus replicates within the cell, and how it hijacks its host machines to release it after multiplication,” said Schwab. Until now, little was known about the origin and development of the effects that SARS-CoV-2 causes in the human body. This includes a lack of knowledge about the mechanism by which infection leads to the death of infected cells. Having this information will now foster the development of therapies thus reducing virus duplication and, therefore, disease severity.
The team has ensured that the information gathered and, in particular, the unprecedented repository of 3D structural information about virus-induced infrastructures is accessible to all. “I think we are setting a precedent on the fact that we share all the data we have produced with the scientific community. It represents an impressive resource for the community, ”said Yannick Schwab. “This way we can support the global effort to study how SARS-CoV-2 interacts with its host.” The team hopes that the information they have gathered will help develop antiviral drugs.
The team managed to produce the study in an incredibly short time, despite the challenging circumstances. “Half the world – and of course Heidelberg too – was in full swing and we had to improvise almost daily to adjust to the situation. Whether at EMBL or at home, everyone was deeply involved and generously giving their time and deep knowledge, ”said Schwab. “The speed with which we have been working, and the amount of data generated, is astonishing.”
Reference: “Integrative imaging reveals reshaping of SARS-CoV-2 subcellular morphologies” by Mirko Cortese, Ji-Young Lee, Berati Cerikan, Christopher J.Neufeldt, Viola MJOorschot, Sebastian Köhrer, Julian Hennies, Nicole L.Schieber, Paolo Ronchi, Giulia Mizzon, Inés Romero Brey, Rachel Santarella-Mellwig, Martin Schorb, Mandy Boermel, Karel Mocaer, Marianne S.Beckwith, Rachel M.Templin, Viktoriia Gross, Constantin Pape, Christian Tischer, Jamie Frankish, Natalie K.Horvat , Vibor Laketa, Megan Stanifer, Steeve Boulant, Alessia Ruggieri, Laurent Chatel-Chaix, Yannick Schwab and Ralf Bartenschlager, 17 November 2020, Cell Host & Microbe.
DOI: 10.1016 / j.chom.2020.11.003