A research project at the University of Ulm that looked at the corona virus in more detail shows: The exchange of an amino acid allows the bat virus RaTG13 to interact with human cells.
The bat virus RaTG13 is a close relative of SARS-CoV-2, but unlike the causative agent of the COVID-19 pandemic, RaTG13 can only dock poorly onto human cells. However, the exchange of a single amino acid in the spike protein of this bat coronavirus is sufficient for it to bind to human cells via the ACE2 receptor in a similar way to SARS-CoV-2. This was shown in a study from the Institute of Molecular Virology at the University Hospital Ulm, which was recently published in the journal Nature Communications. Another result of the work: A vaccination against SARS-CoV-2 can possibly help to prevent such pathogens from jumping from animals to humans and thus prevent future zoonoses.
The causative agent of the COVID-19 pandemic, SARS-CoV-2, was most likely transmitted directly or via an intermediate host from bats to humans. The virus was able to spread so rapidly in the human population because it effectively infects human lung cells. What characteristics enable bat viruses to jump to humans is currently poorly understood. What is known is that SARS-CoV-2 with its spike protein can dock to the ACE2 receptor of human cells and thus penetrate the cells. A research team led by the virologist Professor Frank Kirchhoff from Ulm has now shown that the exchange of a single amino acid in the spike protein of the bat virus RaTG13 is sufficient for this protein to dock to human cells via the ACE2 receptor and lead to their infection. The results were published in the renowned journal Nature Communications.
“The targeted mutation of an amino acid in the spike protein of RaTG13, more precisely at position 403, allows this bat coronavirus to dock to the same receptor as SARS-CoV-2: the human ACE2 receptor,” explains Professor Frank Kirchhoff, head of the Institute of Molecular Virology at Ulm University Hospital. The research team was also able to reveal the basic mechanism that explains why the ACE2 receptor suddenly has such an attractive effect on the modified spike protein: “The exchanged amino acid in the spike protein of the virus is positively charged and interacts with a negatively charged amino acid in the human ACE2 receptor molecule,” says Fabian Zech, first author of the study and doctoral student at the Institute of Molecular Virology.
The scientific work is a perfect example of the interdisciplinary interaction of experimental laboratory work and theoretical computer modelling. On the one hand, the virus researchers from Ulm changed the amino acid composition of the spike protein of the virus through the targeted generation of mutations (mutagenesis). On the other hand, computer-assisted modelling helped to clarify protein structures and protein-protein interactions. These were carried out by Dr. Christoph Jung from Professor Timo Jacob’s Institute for Electrochemistry at the University of Ulm. So-called reactive force field methods were used to gain insights into the physicochemical properties and interaction energies.
In this scientific work, the virologists from Ulm not only succeeded in enabling the spike protein of the bat coronavirus RaTG13 to infect human cells by means of genetic engineering. They were also able to demonstrate that a reverse mutation in SARS-CoV-2 (R403T) weakens the pandemic agent and reduces viral infection of human cells. This result suggests that the positively charged amino acid is important for the high transmissibility of SARS-CoV-2.
The research project has shown which properties of coronaviruses are crucial for them to be able to jump to humans as zoonoses. The results thus help to better assess the risk of future viral pandemics. And there is another aspect that makes the study interesting: the researchers also investigated whether current vaccinations against SARS-CoV-2 can protect against closely related bat viruses and thus against future zoonoses. The result: “The sera of people who were vaccinated against COVID-19 were able to effectively render the bat virus harmless. The SARS-CoV-2 vaccination could therefore help prevent such viral pathogens from spreading to humans in the future,” the researchers said.
Virus researchers and infection biologists from Erlangen-Nuremberg, Munich and Göttingen as well as other Ulm scientists from electrochemistry, internal medicine and medical microbiology were involved in this research project of the Ulm Institute of Molecular Virology. The study – which has already been published as a preprint and met with great interest – was supported by the DFG (including from the Heisenberg Programme), the BMBF, the Free State of Bavaria and the International Graduate School of Molecular Medicine (IGradU) at Ulm University. This scientific work was realised within the framework of the Ulm Collaborative Research Centre 1279 “Use of the human peptidome for the development of new antimicrobial and anti-cancer therapeutics”.
Further information:
Prof. Dr. Frank Kirchhoff, Head of the Institute for Molecular Virology at Ulm University Hospital, e-mail: frank.kirchhoff@uni-ulm.de
