Scientists at the Würzburg-based Helmholtz Institute for RNA-based Infection Research (HIRI) and the Helmholtz Centre for Infection Research (HZI) in Braunschweig demonstrate for the first time how ZAP, a protein of the human immune defense system, inhibits the replication mechanism of the SARS-CoV-2 coronavirus and can reduce the viral load by a factor of 20. The findings were published in the journal Nature Communications. They can help develop antiviral agents in the fight against the pandemic.
SARS-CoV-2 and other viruses whose genetic material consists of ribonucleic acids (RNA) use a propagation trick called programmed ribosomal reading frame shift. In the process, these viruses prove to be masters of manipulation: they invade host cells and hijack the process that the cells use to read genetic information from a messenger RNA and produce proteins. The viruses change the reading direction: this allows them to produce their own proteins and multiply.
Looking for ways to stop this propagation trick in the SARS-CoV-2 coronavirus, researchers at HIRI have now identified a restriction factor called ZAP. ZAP (from English: Zinc Finger Antiviral Protein) is already known as an immunomodulatory and antiviral protein: “ZAP is a multifunctional molecule in the immune defense that can calm an exuberant immune response and shut down viral activity,” explains Jun. Prof. Neva Caliskan, research group leader at HIRI and principal investigator of the study.
Sharp decrease in viral load
It has not yet been explored whether and how proteins such as ZAP interfere with the ribosomal reading frame shift of SARS-CoV-2. “The reading frame shift has become evolutionarily established as the core of viral replication. And that’s what makes it an attractive drug target,” says Matthias Zimmer, one of the two first authors of the study. “Interestingly, we were able to demonstrate that ZAP binds to the viral RNA that triggers the reading frame shift,” adds the HIRI PhD student from Caliskan’s research group “Recoding Mechanisms in Infections.”
“ZAP interferes with the structural folding of coronavirus RNA and disrupts the signal that SARS-CoV-2 sends to induce host cells to produce its replication enzymes,” said HIRI PhD student Anuja Kibe, second first author of the study, describing the protein’s antiviral effect. And what’s more: in collaboration with researchers at the HZI in Braunschweig, which HIRI founded together with the Julius Maximilians University of Würzburg, the team was able to demonstrate that host cells with an elevated ZAP level have an approximately 20-fold reduction in the amount of virus. The clustered occurrence – or absence – of the protein could thus also be an indicator of whether a corona infection takes a mild or severe course.
More research is needed to fully understand the molecular mechanisms behind this. But already the study results are extremely promising: “Our findings give us hope that ZAP could be used as a template to develop potential new antiviral agents,” says Caliskan.
About ZAP in the current study
The so-called zinc finger antiviral protein (ZAP for short) is a multifunctional protein of the immune defense and inhibits the replication of certain viruses. It occurs in a short (ZAP-S) and a long form (ZAP-L). The effects described in the current studies refer to ZAP-S.
Original publication:
Zimmer M, Kibe A, Rand U, Pekarek L, Ye L, Buck S, Smyth R, Cicin-Sain L, Caliskan N. The short isoform of the host antiviral protein ZAP acts as an inhibitor of SARS-CoV-2 programmed ribosomal frameshifting. Nature Communications, Dec. 10, 2021. DOI: 10.1038/s41467-021-27431-0
