Researchers from the University of Bonn have discovered a new bacterial compound that can inhibit the replication of the influenza virus.
Viruses use the molecular repertoire of infected host cells and multiply. The researchers wanted to exploit this process to create new ways of treating the influenza virus. A team, led by Professor Hiroki Kato from the Institute of Cardiovascular Immunology at the University Hospital Bonn, have discovered a new bacterial compound that can inhibit the function of the enzyme, methyltransferase MTr1, blocking the virus’s ability to multiply.
The compound has been successfully used in lung tissue preparations and mouse studies The researchers also observed synergistic effects with already approved influenza drugs.
The findings of the study have been published in the journal Science.
Molecular capping and cap-snatching
Once the influenza virus has infected a host cell, they transfer its genetic information in the form of nucleic acids, such as DNA or RNA. This information is used to create new viruses in the host cell.
The infected cell uses its own labelling system to distinguish foreign nucleic acids from its own. For example, the cell’s own RNA is tagged with a ‘molecular cap’ that identifies it as non-hazardous. By doing this, the immune system can react specifically to different threats.
The ‘molecular cap’ is a methylated nucleoside, which is a small molecule attached to the end of the RNA chain. Once the RNA is tagged in this way, it can no longer trigger an immune response. If the RNA is not capped, it is recognised by the immune receptor RIG-I and the immune system is alerted.
The influenza virus has developed a specific mechanism to avoid this immune system response. The virus steals the molecular cap from cellular RNA molecules and transfers it to its own RNA. This process is known as cap-snatching.
The MTr1 enzyme provides cellular mRNA with a cap structure allowing the enzyme to function as the cell’s “nucleic acid labeller”. This study has shown how much the influenza virus depends on the function of MTr1.
The influenza virus relies on cap-snatching
“While other viruses, such as SARS-CoV-2, are able to cap their RNA molecules on their own, influenza viruses rely on stealing existing caps,” said Yuta Tsukamoto, lead author of the paper.
“If the function of MTr1 is disrupted in the cell, there are no caps available to transfer to viral RNA. The activity of MTr1 is thus essential for the replication of the influenza virus in the cell,” he added.
The researchers wanted to exploit this dependence to treat influenza infections. The team searched for inhibitors that could specifically inhibit MTr1. They investigated how the substances in infected tissue could affect the number of virus particles produced. This was tested in mouse models and human lung tissue preparations.
“Among thousands of candidates, we were able to identify a molecule that inhibits MTr1 in human lung explants and also in vivo in mice, curtailing influenza replication,” reported Professor Kato.
The inhibitor in question is a derivative of a natural bacterial product called trifluoromethyl tubercidin (TFMT), which is produced by bacteria of the genus Streptomyces.
In this study, the researchers proved TFMT works alongside approved influenza drugs. They were even able to show a synergistic effect with a number of virus particles produced in the tissue.
“We hope this study will lead to the development of new treatments for influenza,” concluded Professor Kato.
