Infected cells were imaged by focused ion beam scanning electron microscopy, a powerful technique to reveal cell organization at the subcellular level in 3D. In this image, the subvolume of a cell was divided to display membrane-bound organelles (in gray) and double-membrane vesicles (in red) – a virus-specific compartment where the viral genome is heavily replicated. Credit: Julian Haines / EMBL
Learning how SARS-CoV-2 Hijack host cell machinery will help develop therapeutic strategies.
As the global coronavirus epidemic continues, scientists are not only trying to find vaccines and drugs to combat it, but also to constantly learn more about the virus. “We can now expect the coronavirus to be seasonal,” explains Ralph Bartenslager, a professor in the Department of Molecular Virology at the University of Heidelberg. “Thus, there is an urgent need to develop and implement prophylactic and therapeutic strategies against this virus.” In a new study, Bartenslager performed detailed imaging analysis to determine how the virus reprogrammed infected cells by the Schwab team at EMBL Heidelberg and using EMBL’s electron microscopy core facility.
Cells infected with SARS-CoV-2 die quickly in just 24 to 48 hours. This suggests that the virus damages the human cell in such a way that it is re-wired and essentially forces it to produce a viral lineage. The main objective of this project was therefore to identify the morphological changes within this cell that are inherent in this reconstructive programming. Bartenslager explains, “In order to develop drugs that suppress viral replication and the consequences of infection from it, as well as virus-induced cell death, it is necessary to have a good understanding of the biological mechanisms that drive the virus replication cycle. The team used imaging features in EMBL and state-of-the-art imaging techniques to modify the 3D architecture of SARS-Cavi-2-infected cells, as well as cellular architecture caused by viruses.
The team was able to perform 3D reconstruction of whole cells and their subcellular parts. Rolf Bartenslager explains, “We are providing critical insights into the virus-induced structural changes in the human cells we have studied. These images clearly and profoundly alter the endombrane system of infected cells – a system that enables the cell to define different parts and sites. The virus induces membrane changes in such a way that it can produce its own replica organelles. These are mini replication compartments where the viral genome expands enormously. To do this, the virus needs a membrane surface. This is done by absorbing the cellular membrane system and creating organelles, which look very different. Scientists have described it as a huge accumulation of bubbles: two membrane layers that make up a large balloon. Between these balloons – which form very reddish cans – the viral genome is released for multiplication and incorporation into new virus particles.
This surprising change is seen in cells a few hours after infection. “We saw how and where the virus replicates in the cell, and how it hijacks its host machinery to be released after multiplication.” Until now, little was known about the origin and development of the effects that SARS-Cavi-2 produces in the human body. This includes a lack of knowledge about the mechanisms by which infection can lead to the death of infected cells. Having this information now will promote the development of therapies that reduce virus replication and, thus, the severity of the disease.
A portion of the infected cell is observed by transmission electron microscopy, in which SARS-CoV-2-specific structures (in red, from the mirror image on the right) can be detected as early as six hours after infection. The genome of the virus is replicated in a high number of replicas in two membrane layers forming a large balloon (large red structures), forming a very ield red compartment. New viruses (small red structures) are being created by emerging at the interface of the endoplasmic reticulum and the Golgi apparatus. Credit: Yannick Swab / EMBL
The team is convinced that an unprecedented wealth of collected information and, in particular, 3D structural information about virus-induced substructures can be used by everyone. “I believe we are establishing a precedent on the fact that we are sharing all the data we have generated with the scientific community. It is a powerful tool for the community, “says Yannick Schweb. “In this way we can support global efforts to study how SARS-Co-2 interacts with its host.” The team hopes their collected information will help in the development of antiviral drugs.
The team managed to produce the study in a very short time despite challenging circumstances. “Half the world – and of course Heidelberg – was in a complete lockdown and we had to improvise on an almost daily basis to adapt to the situation. Whether at EMBL or at home, everyone was deeply involved and generously gave their time and deep knowledge, ”says Schwab. “The pace at which we’ve worked, and the data that has been created, is remarkable.”
References: “Integrative Imaging SARS-CoV-2″ by Mirko Cortis, G-Young Lee, Berati Serican, Christopher J. Newfeldt, Viola MJ Orscott, Sebastian Kuhrer, Julian Haynes, Nicole L. Chinchi, Palio. Demonstrates recovery of receptors in cellular morphologies. ” , Giulia Mizan, Ins Romero Bray, Rachel Santerella-Melvig, Martin Scorb, Mandy Bormel, Karel Mokaar, Marian S. Beckwith, Rachel M. Templein, Victoria Gross, Konstantin Pep, Christian Tischer, Jamie Frankish, Vitaly K. Horvat Lecta, Megan Stanifer, Steve Boulant, Alessia Rugieri, Laurent Chattel-Checks, Yannick Schweb and Ralph Barten, Cell host and microbe.
DOI: 10.1016 / j.chom.2020.11.003
