• Study reveals the SARS-CoV-2 replication cycle in 3D in human lung cells
• Understanding how SARS-CoV-2 hijacks host cell machineries will help in developing therapeutic strategies, including drugs
• Researchers relied on the imaging facilities at EMBL Heidelberg and state-of-the art imaging techniques
• Results published in Cell Host & Microbe

As the global coronavirus pandemic continues, scientists are not only trying to find vaccines and drugs to combat it, but also to continuously learn more about the virus itself. “By now we can expect the coronavirus to become seasonal,” explains Ralf Bartenschlager, professor in the Department of Infectious Diseases, Molecular Virology, at Heidelberg University. “Thus, there is an urgent need to develop and implement both prophylactic and therapeutic strategies against this virus.” In a new study, Bartenschlager, assisted by the Schwab team at EMBL Heidelberg and using EMBL’s Electron Microscopy Core Facility, performed a detailed imaging analysis to determine how the virus reprograms infected cells.

Cells that become infected by SARS-CoV-2 die rather quickly, within only 24 to 48 hours. This indicates that the virus harms the human cell in such a way that it is rewired and essentially forced to produce viral progeny. The main aim of the project was therefore to identify the morphological changes within a cell that are inherent to this reprogramming. “To develop drugs which suppress the viral replication and thereby the consequence of the infection, as well as the virus-induced cell death, is key to have a better understanding of the biological mechanisms driving the virus’ replication cycle,” explains Bartenschlager. The team used the imaging facilities at EMBL and state-of-the art imaging techniques to determine the 3D architecture of SARS-CoV-2-infected cells, as well as alterations of cellular architecture caused by the virus.

The team was able to create 3D reconstructions of whole cells and their subcellular compartments. “We are providing critical insights into virus-induced structural changes in the studied human cells,” explains Ralf Bartenschlager. The images revealed an obvious 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 replication organelles. These are mini replication compartments where the viral genome is amplified enormously. To do this, the virus requires membrane surfaces. These are created by exploiting a cellular membrane system and creating an organelle, which has a very distinct appearance. The scientists describe it as a massive accumulation of bubbles: two membrane layers forming a big balloon. Within these balloons – which form a very shielded compartment – the viral genomes are multiplied and released to become incorporated into new virus particles.

This striking change can be seen in the cells only a few hours after infection. “We saw how and where the virus replicates within the cell, and how it hijacks its host machinery to be released after multiplication,” Schwab says. 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 the infection leads to the death of infected cells. Having this information now will foster the development of therapies reducing virus replication and, thus, disease severity.

The team has made sure that the collected information and, in particular, the unprecedented repository of 3D structural information about virus-induced substructures can be used by everyone. “I believe we are setting a precedent on the fact that we are sharing all data that we produced with the scientific community. It represents an impressive resource to the community,” says Yannick Schwab. “This way we can support the global effort to study how SARS-CoV-2 interacts with its host.” The team hopes that their collected information will help in the development of 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 as well – were in full lockdown and we had to improvise almost on a daily basis to adapt to the situation. Whether at EMBL or from home, all were deeply involved and generously gave their time and deep knowledge,” says Schwab. “The speed at which we worked, and the amount of data that was produced, is remarkable.”

Related Links

• Schwab team
• AG Bartenschlager
• Department of Infectious Diseases, Molecular Virology at Heidelberg University
• Electron Microscopy Core Facility at EMBL
• EMBL’s contribution to fighting the coronavirus pandemic

Source Articles
Mirko Cortese et al. Integrative imaging reveals SARS-CoV-2 induced reshaping of subcellular morphologies. Cell Host & Microbe, published online on 17 November 2020
DOI: https://doi.org/10.1016/j.chom.2020.11.003

Until now it’s been unclear what regulates the number of tentacles a sea anemone can grow. Scientists from the Ikmi group at EMBL Heidelberg, in collaboration with researchers in the Gibson lab at the Stowers Institute for Medical Research in Kansas City, have shown that the number of tentacles is defined by the amount of food consumed. “Controlling the number of tentacle arms by food intake makes the sea anemone behave more like a plant developing new branches than an animal growing a new limb,” explains group leader Aissam Ikmi. Defining what environmental factors trigger morphological changes is a particularly important question given the longevity of sea anemones, with some species living for more than 65 years. “As predominantly sessile animals, sea anemones must have evolved strategies to deal with environmental changes to sustain such a long lifespan,” adds Ikmi.

The scientists have shown that the growth of new tentacles happens not only when the sea anemone is a juvenile, but also throughout adulthood. “We can conclude that the number of tentacle arms must be determined by the interplay between genetic and environmental factors,” says Ikmi, who started this project when he was still a postdoc in the lab of Matt Gibson. While the sea anemone uses different strategies to build tentacles in the different stages of its life, the final arms are morphologically indistinguishable from each other. “If humans could do the same, it would mean that the more we ate, the more arms and legs we could grow,” says Ikmi. “Imagine how handy it would be if we could activate this when we needed to replace damaged limbs.”

When Ikmi’s group studied the locations at which the new arms form, they found that muscle cells pre-mark the sites of new tentacles. These muscle cells change their gene expression signature in response to food. The same molecular signalling employed to build tentacles in sea anemones also exists in many other species – including humans. So far, however, its role has been studied mainly in embryonic development. “We propose a new biological context in which to understand how nutrient uptake impacts the function of this developmental signalling: a situation that is relevant for defining the role of metabolism in guiding the formation of organs during adulthood” explains Ikmi. “Sea anemones show us that it is possible that nutrients are not converted into excess fat storage – as it is the case in all mammals – but instead transformed into a new body structure.”

While this finding is novel on its own, it also shows that sea anemones, which are traditionally used for evolutionary developmental studies, are well suited to study morphogenesis in the context of organism–environment interactions.

To build the branching map of new tentacles, researchers analysed more than 1000 sea anemones one by one. “Scoring such a massive number of tentacles is, in some ways, a story in itself,” says Mason McMullen, laughing. McMullen, a clinical pharmacist at the University of Kansas Health System, spent months imaging sea anemones’ heads to score their tentacle number and location.

Knowing that the number of tentacles in sea anemones is determined by their food intake, the group plans to define the key nutrients critical to this process. Ikmi and his group also want to further investigate the unconventional role of muscles in defining the sites where new tentacles form. “We’re currently investigating this novel property of muscle cells and are eager to find out the mystery behind them,” he concludes.

Links

• Ikmi group
• Stowers Institute for Medical Research
• University of Kansas Health System

Source Article
Aissam Ikmi et al. Feeding-dependent tentacle development in the sea anemone Nematostella vectensis. Nature communications, published on 2 September 2020
DOI: 10.1038/s41467-020-18133-0