- Assistant Professor
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.
Selected Publications —
L.S. Voth, J. O’Connor, C.M. Kerr, E. Doerger, N. Schwarting, P. Sperstad, D. K. Johnson, and A.R. Fehr. 2021. Unique mutations in the MHV macrodomain differentially attenuate virus replication, indicating multiple roles for the macrodomain in coronavirus replication. J. Virol. July 12;95(15):e0076621. doi: 10.1128/JVI.00766-21.
Y.M.O. Alhammad, M.M. Kashipathy, A. Roy, J.P. Gagne, P. McDonald, P. Gao, L. Nonfoux, K.P. Battaile, D.K. Johnson, E.D. Holmstrom, G.G. Poirier, S. Lovell, and A.R. Fehr. 2020. The SARS-CoV-2 conserved macrodomain is a mono-ADP-ribosylhydrolase. J Virol. Jan. 13; 95(3):e01969-20. doi: 10.1128/JVI.01969-20.
C.D. Heer, L.S. Voth, D.J. Sanderson, Y.M.O. Alhammad, M.S. Schmidt, S.A.J. Trammell, S. Perlman, M.S. Cohen, A.R. Fehr#, and C. Brenner#. 2020. Coronavirus and PARP expression dysregulate the NAD Metabolome: a potentially actionable component of innate immunity. J Biol Chem.295(52):17986-17996. Doi:10.1074/jbc.RA120.015138
M.E. runewald, M.G. Shaban, S.R. Mackin, A.R. Fehr, and S. Perlman. 2020. Murine coronavirus infection activates AhR in an IDO1-independent manner contributing to cytokine modulation and pro-viral TiPARP expression. J Virol. 94(3) e01743-19. Doi:10.1128/JVI.01743-19
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.
Y.M.O. Alhammad, A.R.Fehr. 2020. The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation. Viruses. 2020 Mar 31;12(4).
A.R. Fehr#, 2020. S.A. Singh, C.M. Kerr, S. Mukai, H. Higashi, and M. Aikawa#. 2020. The impact of PARPs and ADP-ribosylation on inflammation and host-pathogen interactions. Genes Dev. 2020 Mar 1;34(5-6):341-359.
A.R. Fehr. 2020. Bacterial Artificial Chromosome-Based Lambda Red Recombination with the I-SceI Homing Endonuclease for Genetic Alteration of MERS-CoV. Methods Mol. Biol. 2020; 2099:53-68
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