Natural variation influences virus-relevant proteins
Berlin, 16.12.2020 – Joint press release of Charité – Universitätsmedizin Berlin and Berlin Institute of Health (BIH)
Like all viruses, the new coronavirus is dependent on the help of the human host cell. The function carriers of the cell, the proteins, act as receptors to enable the virus to enter the host cell or help it to multiply. Scientists from the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH), together with colleagues from Great Britain, Germany, and the USA, have now investigated the corresponding genes of the helper proteins in a large study. In the process, they came across a large number of variants that influence the quantity or function of the proteins and thus also their ability to support the virus. They thus reveal possible target structures for new drugs. The researchers have now published their results in the journal Nature Communications*.
An infection with the new coronavirus SARS-CoV-2 proceeds – like every viral infection – according to a certain pattern: First, the viruses bind to receptor proteins on the surface of the human host cells in the throat, nose, or lungs, then they enter the cell, where they multiply with the help of the host cell machinery. The newly formed virus particles cause the infected cell to burst and infect other cells. As soon as the immune system notices what is happening, a defence mechanism is set in motion with the aim of destroying and removing both the viruses and the virus-infected cells. If everything runs smoothly, the infection is usually over after two weeks. For all these processes, however, the virus depends on proteins from the human or host.
“In severe cases of COVID-19, this regulated process is out of control and the immune system causes an excessive inflammatory reaction that not only attacks virus-infected cells, but also healthy tissue,” says Prof. Dr. Claudia Langenberg, BIH Professor of Computational Medicine and head of the newly published study. “Naturally occurring variations in the genes that influence the blueprint for these human proteins can alter their concentration or function and thus be a cause for the different course of the disease,” says Prof. Langenberg. The team is familiar with genetic variants that influence the concentration or structure of proteins and other molecules in human blood. “As molecular epidemiologists, we study the diversity in the genes, i.e., the building instructions of the proteins of entire populations, in order to uncover susceptibilities to diseases whose cause lies in the interaction of many small deviations,” explains the scientist, who only moved to BIH in September from the Medical Research Council Epidemiology Unit at the University of Cambridge. “We now wanted to use these experiences and data sets for the COVID-19 epidemic and make them available to the scientific community.”
“We screened 179 proteins known to be involved in SARS-CoV-2 infection for their naturally occurring variants,” reports Dr Maik Pietzner, first author of the study and a scientist with Prof Langenberg in the lab. “We were already able to draw on results based on samples from the first COVID-19 patients at Charité.” This was possible thanks to the close cooperation with the working group of Prof. Dr. Markus Ralser, Director of the Institute of Biochemistry at Charité, which had already been able to publish results on this. Prof. Langenberg’s team was able to use data from an extensive population study, the MRC Fenland Cohort, which contains information from more than 10,000 study participants. They discovered 38 targets for drugs already available, as well as evidence that certain proteins that interact with the virus also influence the immune system. “Our results also help to better understand the risk factors for the sometimes-severe courses of COVID-19. We were able to show that blood coagulation proteins are influenced by the same genetic variant that also increases the risk of contracting COVID-19 and that causally determines blood group 0,” reports Dr. Pietzner.
The team immediately made the results publicly available on a web server developed with colleagues at Helmholtz Zentrum München (https://omicscience.org/apps/covidpgwas/). Since then, scientists all over the world have been using the data to identify target structures for new drugs or to better understand the course of COVID-19. “Even before our work was officially published, articles have already appeared that make use of our findings,” says Prof. Langenberg happily. “This is exactly what we were hoping for!”