We study how RNA viruses amplify, mutate, and cause disease

In 1918, the Spanish Flu killed 50-100 million people. Unfortunately, equally devastating viruses can emerge at any moment. In the 21st century, we have already seen outbreaks of the Ebola virus, avian influenza (H5N1 and H7N9), coronaviruses (SARS-CoV, SARS-CoV-2 and MERS-CoV) and Zika. In addition, viruses are costly: influenza alone costs the USA $90 billion per year. Clearly, we need to gain a better understanding of how these viruses amplify themselves in humans and how they cause disease.

The amplification of an RNA virus relies on the activity of an enzyme called the RNA polymerase (te Velthuis et al, Nature Rev Microbiol 2021). We use biochemical, virological, structural and single-molecule techniques to study how this viral enzyme works (an engineering problem) and how its activity contributes to the ability of RNA viruses to cause disease (a cell biology/virology/immunology problem). In addition, we study how inhibitors of viral replication work.

One of our key recent findings shows that the RNA polymerase from highly pathogenic viruses makes a lot of short aberrant RNA molecules, which we call mini viral RNAs (te Velthuis et al, Nature Microbiol 2018). A subset of the these mini viral RNAs contains an RNA structure that contributes to activation of the innate immune response (French et al, Science Advances 2022).

We are currently working on methods to screen for innate immune-inducing mini viral RNAs in patients, figuring our how they are made and if we can inhibit this, and we are investigating how they interact exactly with our immune response.