Anthony Fehr
The impact of ADP-ribosylation on Coronavirus replication and pathogenesis
Coronaviruses (CoVs) are significant pathogens of both veterinary and clinical importance. Some, such as Porcine Epidemic Diarrhea Virus (PEDV) and Infectious Bronchitis Virus (IBV), cause epidemics and lethal disease in veterinary animals. In addition, the highly pathogenic human coronaviruses SARS-CoV and MERS-CoVs recently have emerged into the human population from intermediate hosts and caused large outbreaks of often fatal severe respiratory disease. It is likely that CoVs will continue to cross species barriers due to their high prevalence in nature and their ability to recombine and infect new species. Therefore, it is imperative to further understand the biology of CoVs and develop novel surveillance strategies, therapeutics, and vaccines.
CoVs are large, positive-sense RNA viruses with genomes of ~30 kb and are composed of structural, nonstructural, and accessory proteins. Several of the nonstructural proteins have important roles in antagonizing the innate immune response; however, their mechanisms of action remain largely unknown. My lab is especially interested in the CoV macrodomain, a small evolutionarily conserved domain within nonstructural protein 3 (nsp3) that removes ADP-ribose, a post-translational modification, from proteins. We showed that the macrodomain is essential for CoV pathogenesis by promoting virus replication in vivo and blocking the IFN response. More recently we have demonstrated that the CoV macrodomain reverses anti-viral ADP-ribosylation mediated by PARP (poly-ADP-ribose polymerase) enzymes.
My primary research interests lie in dissecting how viruses counter anti-viral measures imposed by their hosts, focusing on the interactions between cellular PARP enzymes and viral macrodomains. Initial studies will use CoVs as model to study these interactions and will be expanded to identify interactions between PARPs and other viruses in the future. Identifying specific antiviral PARPs, the targets of both the PARPs and macrodomains during infection, and the biological effects of ADP-ribosylation are significant questions in this field. I am also interested in examining the role of additional virus factors, such as the CoV packaging signal, in evading the innate immune response. My lab will address these questions using a variety of unique molecular virology, genetic, and biochemical/chemical biology approaches.
Selected publications:
M.E. Grunewald, Y. Chen, C. Kuny, T. Maejima, R. Lease, D. Ferraris, M. Aikawa, C.S. Sullivan, S. Perlman, and A.R. Fehr. 2019. The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. PLoS Pathog 15(5):e1007756 [Highlighted with a press release posted to EurekAlert]
R. Channappanavar, A.R. Fehr, J. Zheng, C. Wohlford-Lenane, J.E. Abrahante, M. Mack, R. Sompallae, P.B. McCray Jr., D.K. Meyerholz, and S. Perlman. 2019. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest. 130:126363
J. Athmer*, A.R.Fehr*, M.E. Grunewald, D. Wheeler, K. Graepel, R. Channapannavar, A Sekine, M. Gale Jr., M.R. Denison, and S. Perlman. 2017. Selective packaging in murine coronavirus promotes virulence by limiting type-I IFN responses. mBio. 9:e00272-18.
M.E. Grunewald, A.R. Fehr, J. Athmer, and S. Perlman. 2017. The coronavirus nucleocapsid protein is ADP-ribosylated. Virology. pii: S0042-6822(17)30399-9.
J. Canton*, A.R. Fehr*, R. Fernandez-Delgado, F. J. Gutierrez-Alvarez, M.T. Sanchez-Aparicio, A. Garcia-Sastre, S. Perlman, L. Enjuanes, and I. Sola. 2017. MERS-CoV 4b protein interferes with the NF-κB innate immune response during infection. PLoS Pathog. 14(1):e1006838.
J. Athmer, A.R. Fehr, M. Grunewald, E.C. Smith, M.R. Denison, and S. Perlman. 2017. In situ tagged nsp15 reveals nsp15 interactions with coronavirus replication/ transcription complex associated proteins. mBio 8:e02320-16.
A.R. Fehr, R. Channappanavar, G. Jankevicious, C. Fett, J. Zhao, J. Athmer, D. K. Meyerholz, Ivan Ahel, and S. Perlman. 2016. The conserved coronavirus macrodomain promotes virulence and suppresses the innate immune response during severe acute respiratory syndrome coronavirus infection. mBio 7:e01721-16.
R. Channappanavar, A.R. Fehr, R. Vijay, M. Mack, J. Zhao, D.K. Meyerholz, and S. Perlman. 2016. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host & Microbe 19:181-193.
A.R. Fehr, J. Athmer, R. Channappanavar, J.M. Phillips, D.K. Meyerholz, and S. Perlman. 2015. The nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis. J Virol. 89:1523-1536.
Review articles:
A.R. Fehr*, G. Jankevicius*, I. Ahel, and S. Perlman. 2017. Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis. Trends Microbiol. 2018. 26(7):598-610
A.R. Fehr*, R. Channapannavar* and S. Perlman. 2017. Middle East Respiratory Syndrome: Emergence of a pathogenic human coronavirus. Annu. Rev. Med. 2017. 68:387-99
A.R. Fehr and S. Perlman. 2015. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol. Biol. 1282:1-23.
*These authors contributed equally to this manuscript
