Anthony R Fehr

Anthony Fehr
  • Associate Professor
  • MB Research Coordinator
He/him/his

Contact Info

785-864-6626
8041 Haworth

Personal Links

Biography —

My primary research interest is in studying the complex interplay between the host innate immune system and virus infections. We focus on how post-translational modifications contribute to the innate anti-viral response and how viral proteins specifically counteract these responses, using coronaviruses as a model. To address these research questions, we use a variety of molecular, biochemical, and virological techniques.

I graduated from the University of Nebraska-Lincoln in 2005 with a B.S. in biochemistry where I began studying viruses in the lab of Dr. James Van Etten. I then obtained a PhD in Molecular Microbiology from Washington University-St. Louis in 2011 where I studied the molecular virology of human cytomegalovirus under the mentorship of Dr. Dong Yu. I then moved to the University of Iowa as a post-doc to study coronavirus replication and pathogenesis under Dr. Stanley Perlman. In 2018 I started my own lab at KU to continue studying coronaviruses.

I am currently an associate professor in the Department of Molecular Biosciences where I serve as the research coordinator.

Education —

Post-doc in Virology, University of Iowa, 2018
Ph.D. in Virology, Washington University-St. Louis, 2011
B.S. in Biochemistry, University of Nebraska-Lincoln, 2005

Research —

Post-translation modifications (PTMs), or the addition of small molecules to quickly change their function, are critical for the hosts anti-viral response. ADP-ribosylation is a PTM that is induced upon virus infection, but there is still relatively little known about how ADP-ribosylation inhibits virus replication. ADP-ribosylation requires the activity of host PARP enzymes that add ADP-ribose to proteins, while other proteins, including macrodomains, act to remove the modification. Interestingly, coronaviruses (CoVs) all encode for a macrodomain, termed Mac1, which removes ADP-ribose from proteins. This indicates that CoVs may be especially sensitive to the antiviral functions of ADP-ribosylation. Using a robust BAC-based reverse genetics platform to make genetic changes to the CoV genome, we have shown that in the absence of Mac1 activity CoVs replicate poorly, especially in vivo, and do not cause disease in animal models of infection. These results demonstrate that without Mac1, the host can control CoV infection, and thus understanding how ADP-ribosylation functions to limit CoV replication may lead to the development of novel methods for controlling CoV infections, including Mac1 inhibitors or live-attenuated vaccines. We are currently studying many of the molecular factors involved in this unique host-virus interaction to better understand how ADP-ribosylation contributes to the anti-viral response and how CoVs thwart this response. Some of the projects in the lab include:

Determine the mechanisms that PARP14 uses to inhibit virus infection and promote the innate immune response.

Our research has demonstrated, using KO cells, a highly specific inhibitor, and expressing plasmids that PARP14 both represses CoV replication and promotes interferon (IFN) production following infection. In addition, we have found that PARP14 also represses HSV-1 replication but promotes the replication of Ebola and Nipah virus. Furthermore, we have engineered PARP14 knockout mice to explore the role of PARP14 in mouse infections. Using these and other molecular and biochemical tools, we are now poised to identify specific targets of PARP14 and determine how they impact virus replication and IFN production both in cells and in mice.

Determine how both the ADP-ribose binding and eraser activities of Mac1 promote virus replication.

Our lab has developed multiple biochemical assays to measure Mac1 ADP-ribose binding and removing activities. We can use these assays to identify residues that separately impact these functions and ultimately define how the biochemical activities contribute to virus replication. For instance, we have identified an aspartic acid residue that is critical for ADP-ribose binding, while a separate asparagine residue is critical for enzyme activity. Using these mutations, we’ve shown that ADP-ribose binding is critical for virus transcription while the enzyme activity is important for translation of viral proteins. We are currently probing other Mac1 residues for their impact on the biochemical and virological functions of Mac1.

Develop novel inhibitors and vaccines targeting the CoV macrodomain.

Coronaviruses lacking Mac1 are highly attenuated in cell culture and in mice, and thus make an attractive therapeutic target. Over the past 5 years, we have developed a high-throughput screening assay to identify compounds that inhibit Mac1. We currently have developed several moderately potent Mac1 inhibitors and were the first to demonstrate that Mac1 inhibitors can repress CoV replication in cell culture. We are currently working to improve the efficacy of these inhibitors and eventually test them in mice.

We have also leveraged the fact that Mac1 mutant viruses are highly attenuated in the design of a live-attenuated vaccine for SARS-CoV-2. A full deletion of Mac1 in SARS-CoV-2 replicates well in cells but is extremely attenuated in mice. We have demonstrated that prior infection with the Mac1 deletion virus protects from infection with WT virus. We are currently working with collaborators to further determine how effective this vaccine is at inducing protective immunity and to develop an even safer vaccine by incorporating additional mutations.

Teaching —

  • BIOL512 Virology (Spring)
  • BIOL814 Advanced Virology (Spring, even years)
  • BIOL807 Molecular Biosciences (Fall)
  • BIOL925 Grant Writing (Fall)

My classroom teaching has focused on teaching virology at both the undergraduate and graduate levels, including BIOL512, BIOL814, and BIOL807. Undergraduate virology focuses on basic principles of virology at a very detailed level. Graduate virology is fast paced literature-based course which covers basic aspects of virology while teaching methods and data interpretation in primary virology research. I also teach grant writing to 2nd year graduate students in preparation for their qualifying exam. Outside of the classroom I mentor several undergraduate and graduate students, as well as well as post-doctoral trainees in research methods and enable them to do world-class science.

Selected Publications —

See all papers by Anthony R Fehr on PubMed

  1. Parthasarathy S, Saenjamsai P, Hao H, Ferkul A, Pfannenstiel JJ, Suder EL, Bejan DS, Chen Y, Schwarting N, Aikawa M, Mühlberger E, Orozco RC, Sullivan CS, Cohen MS, Davido DJ, Hume AJ, Fehr AR. PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses. bioRxiv [Preprint]. 2024 Apr 26:2024.04.26.591186. doi: 10.1101/2024.04.26.591186. PMID: 38712082; PMCID: PMC11071520.

  2. Kerr CM, Pfannenstiel JJ, Alhammad YM, Roy A, O'Connor JJ, Ghimire R, Khattabi R, Shrestha R, McDonald PR, Gao P, Johnson DK, More S, Channappanavar R, Fehr AR. Mutation of highly conserved residues in loop 2 of the coronavirus macrodomain demonstrates that enhanced ADP-ribose binding is detrimental to infection. bioRxiv [Preprint]. 2024 Jan 4:2024.01.03.574082. doi: 10.1101/2024.01.03.574082. PMID: 38260573; PMCID: PMC10802294.

  3. Wazir S, Parviainen TAO, Pfannenstiel JJ, Duong MTH, Cluff D, Sowa ST, Galera-Prat A, Ferraris D, Maksimainen MM, Fehr AR#, Heiskanen JP#, Lehtiö L#. Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target. J Med Chem. 2024 Apr 9. doi: 10.1021/acs.jmedchem.3c02451. Epub ahead of print. PMID: 38592023.

  4. O'Connor JJ, Ferraris D, Fehr AR. An Update on the Current State of SARS-CoV-2 Mac1 Inhibitors. Pathogens. 2023 Oct 7;12(10):1221. doi: 10.3390/pathogens12101221. PMID: 37887737; PMCID: PMC10610136.

  5. Otter CJ, Bracci N, Parenti NA, Ye C, Asthana A, Blomqvist EK, Tan LH, Pfannenstiel JJ, Jackson N, Fehr AR, Silverman RH, Burke JM, Cohen NA, Martinez-Sobrido L, Weiss SR. SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling. Proc Natl Acad Sci U S A. 2024 Apr 9;121(15):e2320194121. doi: 10.1073/pnas.2320194121. Epub 2024 Apr 3. PMID: 38568967.

  6. Kerr CM, Parthasarathy S, Schwarting N, O'Connor JJ, Pfannenstiel JJ, Giri E, More S, Orozco RC, Fehr AR. PARP12 is required to repress the replication of a Mac1 mutant coronavirus in a cell- and tissue-specific manner. J Virol. 2023 Sep 28;97(9):e0088523. doi: 10.1128/jvi.00885-23. Epub 2023 Sep 11. PMID: 37695054; PMCID: PMC10537751.

  7. O'Connor JJ, Voth L, Athmer J, George NM, Connelly CM, Fehr AR. Two Commercially Available Blood-Stabilization Reagents Serve as Potent Inactivators of Coronaviruses. Pathogens. 2023 Aug 25;12(9):1082. doi: 10.3390/pathogens12091082. PMID: 37764890; PMCID: PMC10534660.

  8. Alhammad YM, Parthasarathy S, Ghimire R, Kerr CM, O'Connor JJ, Pfannenstiel JJ, Chanda D, Miller CA, Baumlin N, Salathe M, Unckless RL, Zuñiga S, Enjuanes L, More S, Channappanavar R#, Fehr AR#. SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice. Proc Natl Acad Sci U S A. 2023 Aug 29;120(35):e2302083120. doi: 10.1073/pnas.2302083120. Epub 2023 Aug 22. PMID: 37607224; PMCID: PMC10468617.

  9. Ly CY, Pfannenstiel J, Pant A, Yang Z, Fehr AR, Rodzkin MS, Davido DJ. Inhibitors of One or More Cellular Aurora Kinases Impair the Replication of Herpes Simplex Virus 1 and Other DNA and RNA Viruses with Diverse Genomes and Life Cycles. Microbiol Spectr. 2023 Feb 14;11(1):e0194322. doi: 10.1128/spectrum.01943-22. Epub 2022 Dec 20. PMID: 36537798; PMCID: PMC9927324.

  10. Parthasarathy S, Fehr AR. PARP14: A key ADP-ribosylating protein in host-virus interactions? PLoS Pathog. 2022 Jun 9;18(6):e1010535. doi: 10.1371/journal.ppat.1010535. PMID: 35679255; PMCID: PMC9182250.

  11. Sherrill LM, Joya EE, Walker A, Roy A, Alhammad YM, Atobatele M, Wazir S, Abbas G, Keane P, Zhuo J, Leung AKL, Johnson DK, Lehtiö L, Fehr AR#, Ferraris D. Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain. Bioorg Med Chem. 2022 Aug 1;67:116788. doi: 10.1016/j.bmc.2022.116788. Epub 2022 May 11. PMID: 35597097; PMCID: PMC9093066.

  12. Roy A, Alhammad YM, McDonald P, Johnson DK, Zhuo J, Wazir S, Ferraris D, Lehtiö L, Leung AKL, Fehr AR. Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening. Antiviral Res. 2022 May 19;203:105344. doi: 10.1016/j.antiviral.2022.105344. Epub ahead of print. PMID: 35598780; PMCID: PMC9119168.

  13. Comar CE, Otter CJ, Pfannenstiel J, Doerger E, Renner DM, Tan LH, Perlman S, Cohen NA, Fehr AR, Weiss SR. MERS-CoV endoribonuclease and accessory proteins jointly evade host innate immunity during infection of lung and nasal epithelial cells. Proc Natl Acad Sci U S A. 2022 May 24;119(21):e2123208119. doi: 10.1073/pnas.2123208119. Epub 2022 May 20. PMID: 35594398.

  14. Leung AKL, Griffin DE, Bosch J, Fehr AR. The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses. Pathogens. 2022 Jan 14;11(1):94. doi: 10.3390/pathogens11010094. PMID: 35056042; PMCID: PMC8780475.

  15. Voth LS, O'Connor JJ, Kerr CM, Doerger E, Schwarting N, Sperstad P, Johnson DK, Fehr AR. Unique Mutations in the Murine Hepatitis Virus Macrodomain Differentially Attenuate Virus Replication, Indicating Multiple Roles for the Macrodomain in Coronavirus Replication. J Virol. 2021 Jul 12;95(15):e0076621. doi: 10.1128/JVI.00766-21. Epub 2021 Jul 12. PubMed PMID: 34011547; PubMed Central PMCID: PMC8274620. 

  16. Alhammad YMO, Kashipathy MM, Roy A, Gagné JP, McDonald P, Gao P, Nonfoux L, Battaile KP, Johnson DK, Holmstrom ED, Poirier GG, Lovell S, Fehr AR. The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase. J Virol. 2021 Jan 13;95(3). doi: 10.1128/JVI.01969-20. Print 2021 Jan 13. PubMed PMID: 33158944; PubMed Central PMCID: PMC7925111.

  17. Heer CD, Sanderson DJ, Voth LS, Alhammad YMO, Schmidt MS, Trammell SAJ, Perlman S, Cohen MS, Fehr AR#, Brenner C#. Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity. J Biol Chem. 2020 Dec 25;295(52):17986-17996. doi: 10.1074/jbc.RA120.015138. Epub 2020 Oct 13. PubMed PMID: 33051211; PubMed Central PMCID: PMC7834058.

  18. Grunewald ME, Shaban MG, Mackin SR, Fehr AR, Perlman S. Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression. J Virol. 2020 Jan 17;94(3). doi: 10.1128/JVI.01743-19. Print 2020 Jan 17. PubMed PMID: 31694960; PubMed Central PMCID: PMC7000979.

  19. Grunewald ME, Chen Y, Kuny C, Maejima T, Lease R, Ferraris D, Aikawa M, Sullivan CS, Perlman S#, Fehr AR#. The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. PLoS Pathog. 2019 May;15(5):e1007756. doi: 10.1371/journal.ppat.1007756. eCollection 2019 May. PMID: 31095648; PMCID: PMC6521996.

  20. Fehr AR, Jankevicius G, Ahel I, Perlman S. Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis. Trends Microbiol. 2018 Jul;26(7):598-610. doi: 10.1016/j.tim.2017.11.011. Review. PubMed PMID: 29268982; PubMed Central PMCID: PMC6003825.