Anthony Fehr

The outbreaks of several highly pathogenic human coronaviruses (hP-hCoVs), including SARS-CoV-2, SARS-CoV, and MERS-CoV have demonstrated the incredible ability of CoVs to cross species barriers and cause severe infections in humans and other mammalian species. It is likely that CoVs will continue to cross species barriers due to their high prevalence in nature, their ability to manipulate both innate and adaptive responses to infection, and their propensity to recombine and infect new species. Therefore, it is imperative that we identify and develop a wide variety of therapeutic options including novel vaccines, antivirals, and anti-inflammatory drugs to combat the currently circulating CoVs, as well as future outbreaks of related viruses for both humans and animals of veterinary importance.

CoVs are large, positive-sense RNA viruses with genomes of ~30 kb and encode for >30 functional protein domains. My lab is especially interested in the CoV macrodomain, a small evolutionarily conserved domain that removes ADP-ribose, a post-translational modification, from proteins. ADP-ribosylation is mediated by cellular enzymes known as PARPs, and many of the PARPs are induced by virus infection. Importantly, we have previously discovered that the CoV macrodomain directly counters the PARP-mediated anti-viral response. In the absence of the CoV macrodomain, CoVs replication poorly, especially in vivo, and do not cause disease in animal models of infection. These results demonstrate that the macrodomain is a prominent virulence factor and a potential therapeutic target.

Our primary research interests lie in dissecting the host-virus interactions between cellular PARP enzymes and viral macrodomains. This research includes defining PARPs important for the antiviral response to CoVs, identifying the targets of PARPs and the macrodomain, and determining how exactly the macrodomain promotes virus replication and disease at a mechanistic level. In addition, we are developing novel macrodomain inhibitors that could also be used therapeutically to treat CoV infection. We address these questions using a variety of unique molecular virology, genetic, and biochemical/chemical biology approaches.