Helmholtz Centre Munich
What exactly are the molecular interactions between the human host and the COVID-19 virus? On what genetic differences are the different courses of the disease based? And how do the virus variants that are still emerging differ in their host-virus interactions? In order to get to the bottom of these questions, an international research team has created a systematic contact map.
The contact map, published in the journal Nature Biotechnology, includes more than 200 protein-protein contacts, called protein interactions. The international consortium of scientists led by Pascal Falter-Braun, Director at the Helmholtz Munich Institute of Network Biology (INET) and Professor of Microbe-Host Interactions at the Faculty of Biology at the Ludwig-Maximilians-Universität (LMU) in Munich , consisted of teams in Canada, USA, France, Spain and Belgium.
In contrast to previous large-scale studies of protein-protein complexes, the direct protein contacts between the virus and the host could now be precisely identified. “To truly understand the mechanistic links between virus and host, we need to know how the pieces fit together,” says Frederick Roth, professor at the University of Toronto’s Donnelly Center and Sinai Health (Toronto, Canada).
Looking more closely at these newly discovered direct protein links (or ‘contactomes’), the team found pathways of connections between viral proteins and infection-related human genes. For example, they were able to detect connections between certain SARS-CoV-2 proteins and human proteins encoded by regions of the genes that other studies have linked to an increased likelihood of severe COVID-19 disease. They also found links between the viral proteins and human genes involved in metabolic disorders such as obesity and diabetes, among others.
“We already know that genetic differences in humans play a key role in the course and severity of a COVID-19 disease,” says Pascal Falter-Braun, and adds: “Thanks to the identification of the molecular contact points, it is now possible to determine the underlying investigate mechanisms in more detail.”
Initial findings show that important inflammatory signaling pathways are activated directly by the virus. These contacts could help explain the excessive inflammatory response that plays a major role in severe cases of COVID-19.
However, the protein-protein contacts do not only affect human cells and the human immune system. Certain compounds also have a far-reaching effect on SARS-CoV-2, such as the replication of the virus.
According to Falter-Braun, the interaction between the virus and the human cell can be imagined like the virus visiting a restaurant: the guest – the virus – initially only has contact with the waiter. But then the waiter goes into the kitchen, gives the order to the chef, and the virus gets an answer again, in this case the food, which in turn acts on the virus. Depending on which proteins in the human cell – i.e. waiters, cooks, kitchen helpers, and others – encounter which proteins of the virus, the infection and immune reaction can turn out very differently.
“Because of this mutual influence of the protein-protein connections, there are a number of potential new target structures for drugs in our systematic contact map,” says Falter-Braun. The scientists have already been able to confirm the effect of the first substance: The human protein USP25 is recruited to promote certain viral processes and its inhibition in turn significantly reduces the replication of the virus.
“Many of the technologies and collaborations in this study were actually developed for other purposes and then quickly adapted to the COVID-19 pandemic. This underscores the value of investments in basic research,” says Dr. Dae-Kyum Kim, one of the lead authors, who began this work at Sinai Health (Toronto) and continued it as an assistant professor at Roswell Park Comprehensive Cancer Center. To do this, the scientists initially had to put in a lot of effort and use the latest technology, because creating the contact map was like solving a huge puzzle for the international team in phases: the scientists systematically analyzed the reactions of around 30 viral proteins – including the well-known one Spike protein – examined and displayed with around 17,500 human proteins in so-called assays. This results in around 450,000 combinations that they examined. They would never have been able to do it by hand in such a short time. “We used robotics to prepare each plate, each containing multiple assays, so that one protein type was automatically paired with another. And we had a computer program with artificial intelligence carry out the first evaluation of whether there were interactions or not,” says Falter-Braun.
Such a mammoth project required a team effort: “We worked together on an interdisciplinary basis, from molecular biological methods and computer-aided analysis of networks and protein regions to specialist knowledge in virology and innate immunity,” says Falter-Braun. ‘Our expertise in virus-host interactomics coupled with the biology of RNA viruses made it possible to assess the virus’ dependency on direct host partners,’ adds Caroline Demeret of the Institut Pasteur.
The researchers believe that the effort was worth it: The contact map is intended to serve as a platform for the scientific community to examine individual interactions in more detail and to understand their effects on molecular mechanisms and clinical progression, thus uncovering starting points for new therapeutic possibilities .
About the lead scientists:
Prof. Dr. Pascal Falter-Braun, Director, Institute of Network Biology (INET), Helmholtz Munich and Chair of Microbe-Host Interactions, Faculty of Biology Ludwig-Maximilians-University (LMU) Munich, Germany
Prof. Dr. Frederick P. Roth, Donnelly Center for Cellular and Biomolecular Research, University of Toronto and the Lunenfeld-Tanenbaum Research Institute, Sinai Health in Toronto, Canada.
dr Michael A. Calderwood, Dana-Farber Cancer Institute and Scientific Director of the Center for Cancer Systems Biology (CCSB), Boston, USA
Prof. Dr. Marc Vidal, Professor of Genetics, Harvard Medical School and Dana-Farber Cancer Institute and Director of the Center for Cancer Systems Biology (CCSB), Boston, USA
dr Caroline Demeret, leader of the Interactomics Group in the Molecular Genetics of RNA Viruses Unit at the Institut Pasteur, Paris, France
Original publication:
Kim et al. (2022): A proteome-scale map of the SARS-CoV-2 human contactome. Nature Biotechnology. DOI: 10.1038/s41587-022-01475-z
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