Mark R. Denison, M.D.

Professor

mark.denison@vumc.org

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Faculty Appointments
Professor of Pediatrics Professor of Pathology, Microbiology and ImmunologyEdward Claiborne Stahlman Chair in Pediatric Physiology and Cell Metabolism
Education
M.D., Medicine, University of Kansas, Kansas City, KansasB.S., Chemistry, English, University of Kansas, Lawrence, Kansas
Office Address
D-6217 MCN
Vanderbilt University Medical Center
Nashville, TN 37232-2581
Research Description
The Denison Lab studies the replication, pathogenesis and countermeasures of the coronaviruses (CoVs), a family of RNA virus including SARS-CoV, MERS-CoV and the 2019-nCoV coronavirus that is causing worldwide outbreak in 2020. Coronaviruses cause human colds, and since 2003 have had three outbreaks of potentially pandemic respiratory infections. The 2019-nCoV has caused over 17,000 cases in China and over 25 countries. Research and training the laboratory uses the model BSL2 coronavirus murine hepatitis virus (MHV) as well as BSL3 pathogens SARS-CoV, MERS-CoV and nCoV to understand the viral and host determinants of replication, pathogenesis, evolution and countermeasures. Our program has defined: mechanisms of replicase protein expression and processing; a novel RNA proofreading mechanism during CoV replication, and inhibitors of coronavirus replication. Our research is currently supported by multiple NIH grant and contract mechanisms with stable long-term support. We have More than 20 graduate students and postdoctoral fellows have trained in the lab. Graduate students and postdocs have been successful at obtaining F30, F31, F32 and T32 support for their training, and have gone on to research positions in academics, industry and government. Current projects in the lab focus on: 1) mechanisms of virus replication; 2) determinants of coronavirus RNA proofreading and fidelity; 3) the role of recombination in virus evolution; 4) development of antivirals and antibodies as potential therapeutics
Research Keywords
Coronavirus / SARS replication; Virus Cell Biology; Emerging Viruses; Antivirals; Polymerase; RNA Proofreading exonuclease; Viral Pathogenesis; Virus Evolution;
Publications
Graepel KW, Agostini ML, Lu X, Sexton NR, Denison MR. Fitness barriers limit reversion of a proofreading-deficient coronavirus. J. Virol [print-electronic]. 2019 Jul 7/24/2019; PMID: 31341046, PII: JVI.00711-19, DOI: 10.1128/JVI.00711-19, ISSN: 1098-5514.

Brown AJ, Won JJ, Graham RL, Dinnon KH, Sims AC, Feng JY, Cihlar T, Denison MR, Baric RS, Sheahan TP. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res [print-electronic]. 2019 Jun 6/21/2019; 169: 104541. PMID: 31233808, PII: S0166-3542(19)30099-3, DOI: 10.1016/j.antiviral.2019.104541, ISSN: 1872-9096.

Pruijssers AJ, Denison MR. Nucleoside analogues for the treatment of coronavirus infections. Curr Opin Virol [print-electronic]. 2019 Apr; 35: 57-62. PMID: 31125806, PII: S1879-6257(19)30001-X, DOI: 10.1016/j.coviro.2019.04.002, ISSN: 1879-6265.

Wang L, Shi W, Chappell JD, Joyce MG, Zhang Y, Kanekiyo M, Becker MM, van Doremalen N, Fischer R, Wang N, Corbett KS, Choe M, Mason RD, Van Galen JG, Zhou T, Saunders KO, Tatti KM, Haynes LM, Kwong PD, Modjarrad K, Kong WP, McLellan JS, Denison MR, Munster VJ, Mascola JR, Graham BS. Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape. J. Virol [electronic-print]. 2018 May 5/15/2018; 92(10): PMID: 29514901, PMCID: PMC5923077, PII: JVI.02002-17, DOI: 10.1128/JVI.02002-17, ISSN: 1098-5514.

Athmer J, Fehr AR, Grunewald ME, Qu W, Wheeler DL, Graepel KW, Channappanavar R, Sekine A, Aldabeeb DS, Gale M, Denison MR, Perlman S. Selective Packaging in Murine Coronavirus Promotes Virulence by Limiting Type I Interferon Responses. MBio. 2018 May 5/1/2018; 9(3): PMID: 29717007, PMCID: PMC5930304, PII: mBio.00272-18, DOI: 10.1128/mBio.00272-18, ISSN: 2150-7511.

Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, Baric RS, Denison MR. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. MBio. 2018 Mar 3/6/2018; 9(2): PMID: 29511076, PMCID: PMC5844999, PII: mBio.00221-18, DOI: 10.1128/mBio.00221-18, ISSN: 2150-7511.

Case JB, Li Y, Elliott R, Lu X, Graepel KW, Sexton NR, Smith EC, Weiss SR, Denison MR. Murine Hepatitis Virus nsp14 Exoribonuclease Activity Is Required for Resistance to Innate Immunity. J. Virol [electronic-print]. 2018 Jan 1/1/2018; 92(1): PMID: 29046453, PMCID: PMC5730787, PII: JVI.01531-17, DOI: 10.1128/JVI.01531-17, ISSN: 1098-5514.

Graepel KW, Lu X, Case JB, Sexton NR, Smith EC, Denison MR. Proofreading-Deficient Coronaviruses Adapt for Increased Fitness over Long-Term Passage without Reversion of Exoribonuclease-Inactivating Mutations. MBio. 2017 Nov 11/7/2017; 8(6): PMID: 29114026, PMCID: PMC5676041, PII: mBio.01503-17, DOI: 10.1128/mBio.01503-17, ISSN: 2150-7511.

Pallesen J, Wang N, Corbett KS, Wrapp D, Kirchdoerfer RN, Turner HL, Cottrell CA, Becker MM, Wang L, Shi W, Kong WP, Andres EL, Kettenbach AN, Denison MR, Chappell JD, Graham BS, Ward AB, McLellan JS. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2017 Aug 8/29/2017; 114(35): E7348-E7357. PMID: 28807998, PMCID: PMC5584442, PII: 1707304114, DOI: 10.1073/pnas.1707304114, ISSN: 1091-6490.

Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017 Jun 6/28/2017; 9(396): PMID: 28659436, PMCID: PMC5567817, PII: 9/396/eaal3653, DOI: 10.1126/scitranslmed.aal3653, ISSN: 1946-6242.

Arabi YM, Balkhy HH, Hayden FG, Bouchama A, Luke T, Baillie JK, Al-Omari A, Hajeer AH, Senga M, Denison MR, Nguyen-Van-Tam JS, Shindo N, Bermingham A, Chappell JD, Van Kerkhove MD, Fowler RA. Middle East Respiratory Syndrome. N. Engl. J. Med. 2017 Feb 2/9/2017; 376(6): 584-94. PMID: 28177862, PMCID: PMC5362064, DOI: 10.1056/NEJMsr1408795, ISSN: 1533-4406.

Athmer J, Fehr AR, Grunewald M, Smith EC, Denison MR, Perlman S. In Situ Tagged nsp15 Reveals Interactions with Coronavirus Replication/Transcription Complex-Associated Proteins. MBio. 2017 Jan 1/31/2017; 8(1): PMID: 28143984, PMCID: PMC5285509, PII: mBio.02320-16, DOI: 10.1128/mBio.02320-16, ISSN: 2150-7511.

Mounce BC, Cesaro T, Moratorio G, Hooikaas PJ, Yakovleva A, Werneke SW, Smith EC, Poirier EZ, Simon-Loriere E, Prot M, Tamietti C, Vitry S, Volle R, Khou C, Frenkiel MP, Sakuntabhai A, Delpeyroux F, Pardigon N, Flamand M, Barba-Spaeth G, Lafon M, Denison MR, Albert ML, Vignuzzi M. Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses. J. Virol [electronic-print]. 2016 Nov 11/1/2016; 90(21): 9683-92. PMID: 27535047, PMCID: PMC5068521, PII: JVI.01347-16, DOI: 10.1128/JVI.01347-16, ISSN: 1098-5514.

Sexton NR, Smith EC, Blanc H, Vignuzzi M, Peersen OB, Denison MR. Homology-Based Identification of a Mutation in the Coronavirus RNA-Dependent RNA Polymerase That Confers Resistance to Multiple Mutagens. J. Virol [electronic-print]. 2016 Aug 8/15/2016; 90(16): 7415-28. PMID: 27279608, PMCID: PMC4984655, PII: JVI.00080-16, DOI: 10.1128/JVI.00080-16, ISSN: 1098-5514.

Case JB, Ashbrook AW, Dermody TS, Denison MR. Mutagenesis of S-Adenosyl-l-Methionine-Binding Residues in Coronavirus nsp14 N7-Methyltransferase Demonstrates Differing Requirements for Genome Translation and Resistance to Innate Immunity. J. Virol [electronic-print]. 2016 Aug 8/15/2016; 90(16): 7248-56. PMID: 27252528, PMCID: PMC4984653, PII: JVI.00542-16, DOI: 10.1128/JVI.00542-16, ISSN: 1098-5514.

Mainou BA, Ashbrook AW, Smith EC, Dorset DC, Denison MR, Dermody TS. Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry. J. Virol [print-electronic]. 2015 Sep; 89(17): 8701-12. PMID: 26109733, PMCID: PMC4524060, PII: JVI.00739-15, DOI: 10.1128/JVI.00739-15, ISSN: 1098-5514.

Tomar S, Johnston ML, St John SE, Osswald HL, Nyalapatla PR, Paul LN, Ghosh AK, Denison MR, Mesecar AD. Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS. J. Biol. Chem [print-electronic]. 2015 Aug 8/7/2015; 290(32): 19403-22. PMID: 26055715, PMCID: PMC4528106, PII: M115.651463, DOI: 10.1074/jbc.M115.651463, ISSN: 1083-351X.

Wang L, Shi W, Joyce MG, Modjarrad K, Zhang Y, Leung K, Lees CR, Zhou T, Yassine HM, Kanekiyo M, Yang ZY, Chen X, Becker MM, Freeman M, Vogel L, Johnson JC, Olinger G, Todd JP, Bagci U, Solomon J, Mollura DJ, Hensley L, Jahrling P, Denison MR, Rao SS, Subbarao K, Kwong PD, Mascola JR, Kong WP, Graham BS. Evaluation of candidate vaccine approaches for MERS-CoV. Nat Commun. 2015 Jul 7/28/2015; 6: 7712. PMID: 26218507, PMCID: PMC4525294, PII: ncomms8712, DOI: 10.1038/ncomms8712, ISSN: 2041-1723.

Smith EC, Case JB, Blanc H, Isakov O, Shomron N, Vignuzzi M, Denison MR. Mutations in coronavirus nonstructural protein 10 decrease virus replication fidelity. J. Virol [print-electronic]. 2015 Jun; 89(12): 6418-26. PMID: 25855750, PMCID: PMC4474304, PII: JVI.00110-15, DOI: 10.1128/JVI.00110-15, ISSN: 1098-5514.

Beachboard DC, Anderson-Daniels JM, Denison MR. Mutations across murine hepatitis virus nsp4 alter virus fitness and membrane modifications. J. Virol [print-electronic]. 2015 Feb; 89(4): 2080-9. PMID: 25473044, PMCID: PMC4338892, PII: JVI.02776-14, DOI: 10.1128/JVI.02776-14, ISSN: 1098-5514.

Smith EC, Sexton NR, Denison MR. Thinking Outside the Triangle: Replication Fidelity of the Largest RNA Viruses. Annu Rev Virol [print-electronic]. 2014 Nov; 1(1): 111-32. PMID: 26958717, DOI: 10.1146/annurev-virology-031413-085507, ISSN: 2327-056X.

Freeman MC, Peek CT, Becker MM, Smith EC, Denison MR. Coronaviruses induce entry-independent, continuous macropinocytosis. MBio. 2014 Aug 8/5/2014; 5(4): e01340-14. PMID: 25096879, PMCID: PMC4128357, PII: mBio.01340-14, DOI: 10.1128/mBio.01340-14, ISSN: 2150-7511.

Khuri-Bulos N, Payne DC, Lu X, Erdman D, Wang L, Faouri S, Shehabi A, Johnson M, Becker MM, Denison MR, Williams JV, Halasa NB. Middle East respiratory syndrome coronavirus not detected in children hospitalized with acute respiratory illness in Amman, Jordan, March 2010 to September 2012. Clin. Microbiol. Infect [print-electronic]. 2014 Jul; 20(7): 678-82. PMID: 24313317, PMCID: PMC4618562, PII: S1198-743X(14)61157-5, DOI: 10.1111/1469-0691.12438, ISSN: 1469-0691.

Freeman MC, Graham RL, Lu X, Peek CT, Denison MR. Coronavirus replicase-reporter fusions provide quantitative analysis of replication and replication complex formation. J. Virol [print-electronic]. 2014 May; 88(10): 5319-27. PMID: 24623413, PMCID: PMC4019139, PII: JVI.00021-14, DOI: 10.1128/JVI.00021-14, ISSN: 1098-5514.

Agnihothram S, Gopal R, Yount BL, Donaldson EF, Menachery VD, Graham RL, Scobey TD, Gralinski LE, Denison MR, Zambon M, Baric RS. Evaluation of serologic and antigenic relationships between middle eastern respiratory syndrome coronavirus and other coronaviruses to develop vaccine platforms for the rapid response to emerging coronaviruses. J. Infect. Dis [print-electronic]. 2014 Apr 4/1/2014; 209(7): 995-1006. PMID: 24253287, PMCID: PMC3952667, PII: jit609, DOI: 10.1093/infdis/jit609, ISSN: 1537-6613.

Agnihothram S, Yount BL, Donaldson EF, Huynh J, Menachery VD, Gralinski LE, Graham RL, Becker MM, Tomar S, Scobey TD, Osswald HL, Whitmore A, Gopal R, Ghosh AK, Mesecar A, Zambon M, Heise M, Denison MR, Baric RS. A mouse model for Betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant. MBio. 2014 Mar 3/25/2014; 5(2): e00047-14. PMID: 24667706, PMCID: PMC3977350, PII: mBio.00047-14, DOI: 10.1128/mBio.00047-14, ISSN: 2150-7511.

Stobart CC, Sexton NR, Munjal H, Lu X, Molland KL, Tomar S, Mesecar AD, Denison MR. Chimeric exchange of coronavirus nsp5 proteases (3CLpro) identifies common and divergent regulatory determinants of protease activity. J. Virol [print-electronic]. 2013 Dec; 87(23): 12611-8. PMID: 24027335, PMCID: PMC3838113, PII: JVI.02050-13, DOI: 10.1128/JVI.02050-13, ISSN: 1098-5514.

Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog [print-electronic]. 2013 Aug; 9(8): e1003565. PMID: 23966862, PMCID: PMC3744431, PII: PPATHOGENS-D-13-01270, DOI: 10.1371/journal.ppat.1003565, ISSN: 1553-7374.

Beachboard DC, Lu X, Baker SC, Denison MR. Murine hepatitis virus nsp4 N258T mutants are not temperature-sensitive. Virology [print-electronic]. 2013 Jan 1/20/2013; 435(2): 210-3. PMID: 23099203, PMCID: PMC3804408, PII: S0042-6822(12)00499-0, DOI: 10.1016/j.virol.2012.10.001, ISSN: 1096-0341.

Smith EC, Denison MR. Coronaviruses as DNA wannabes: a new model for the regulation of RNA virus replication fidelity. PLoS Pathog [print-electronic]. 2013; 9(12): e1003760. PMID: 24348241, PMCID: PMC3857799, PII: PPATHOGENS-D-13-01960, DOI: 10.1371/journal.ppat.1003760, ISSN: 1553-7374.

Graham RL, Becker MM, Eckerle LD, Bolles M, Denison MR, Baric RS. A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease. Nat. Med [print-electronic]. 2012 Dec; 18(12): 1820-6. PMID: 23142821, PMCID: PMC3518599, PII: nm.2972, DOI: 10.1038/nm.2972, ISSN: 1546-170X.

Smith EC, Denison MR. Implications of altered replication fidelity on the evolution and pathogenesis of coronaviruses. Curr Opin Virol [print-electronic]. 2012 Oct; 2(5): 519-24. PMID: 22857992, PII: S1879-6257(12)00110-1, DOI: 10.1016/j.coviro.2012.07.005, ISSN: 1879-6265.

Stobart CC, Lee AS, Lu X, Denison MR. Temperature-sensitive mutants and revertants in the coronavirus nonstructural protein 5 protease (3CLpro) define residues involved in long-distance communication and regulation of protease activity. J. Virol [print-electronic]. 2012 May; 86(9): 4801-10. PMID: 22345451, PMCID: PMC3347385, PII: JVI.06754-11, DOI: 10.1128/JVI.06754-11, ISSN: 1098-5514.

Denison MR, Graham RL, Donaldson EF, Eckerle LD, Baric RS. Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. RNA Biol [print-electronic]. 2011 Mar; 8(2): 270-9. PMID: 21593585, PMCID: PMC3127101, PII: 15013, DOI: 10.4161/rna.8.2.15013, ISSN: 1555-8584.

Huang IC, Bailey CC, Weyer JL, Radoshitzky SR, Becker MM, Chiang JJ, Brass AL, Ahmed AA, Chi X, Dong L, Longobardi LE, Boltz D, Kuhn JH, Elledge SJ, Bavari S, Denison MR, Choe H, Farzan M. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathog. 2011 Jan 1/6/2011; 7(1): e1001258. PMID: 21253575, PMCID: PMC3017121, DOI: 10.1371/journal.ppat.1001258, ISSN: 1553-7374.

Frangoul H, Domm J, Denison MR, Calder C, Black J. H1N1 infection mimicking the clinical presentation of gastrointestinal GVHD in a patient following allo-SCT. Bone Marrow Transplant [print-electronic]. 2011 Jan; 46(1): 152-3. PMID: 20383217, PII: bmt201066, DOI: 10.1038/bmt.2010.66, ISSN: 1476-5365.

Gadlage MJ, Denison MR. Exchange of the coronavirus replicase polyprotein cleavage sites alters protease specificity and processing. J. Virol [print-electronic]. 2010 Jul; 84(13): 6894-8. PMID: 20427532, PMCID: PMC2903247, PII: JVI.00752-10, DOI: 10.1128/JVI.00752-10, ISSN: 1098-5514.

Dulek DE, Williams JV, Creech CB, Schulert AK, Frangoul HA, Domm J, Denison MR, Chappell JD. Use of intravenous zanamivir after development of oseltamivir resistance in a critically Ill immunosuppressed child infected with 2009 pandemic influenza A (H1N1) virus. Clin. Infect. Dis. 2010 Jun 6/1/2010; 50(11): 1493-6. PMID: 20415572, DOI: 10.1086/652655, ISSN: 1537-6591.

Eckerle LD, Becker MM, Halpin RA, Li K, Venter E, Lu X, Scherbakova S, Graham RL, Baric RS, Stockwell TB, Spiro DJ, Denison MR. Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog. 2010 May; 6(5): e1000896. PMID: 20463816, PMCID: PMC2865531, DOI: 10.1371/journal.ppat.1000896, ISSN: 1553-7374.

Gadlage MJ, Sparks JS, Beachboard DC, Cox RG, Doyle JD, Stobart CC, Denison MR. Murine hepatitis virus nonstructural protein 4 regulates virus-induced membrane modifications and replication complex function. J. Virol [print-electronic]. 2010 Jan; 84(1): 280-90. PMID: 19846526, PMCID: PMC2798404, PII: JVI.01772-09, DOI: 10.1128/JVI.01772-09, ISSN: 1098-5514.

Becker MM, Graham RL, Donaldson EF, Rockx B, Sims AC, Sheahan T, Pickles RJ, Corti D, Johnston RE, Baric RS, Denison MR. Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2008 Dec 12/16/2008; 105(50): 19944-9. PMID: 19036930, PMCID: PMC2588415, PII: 0808116105, DOI: 10.1073/pnas.0808116105, ISSN: 1091-6490.

Gadlage MJ, Graham RL, Denison MR. Murine coronaviruses encoding nsp2 at different genomic loci have altered replication, protein expression, and localization. J. Virol [print-electronic]. 2008 Dec; 82(23): 11964-9. PMID: 18815297, PMCID: PMC2583644, PII: JVI.01126-07, DOI: 10.1128/JVI.01126-07, ISSN: 1098-5514.

Denison MR. Seeking membranes: positive-strand RNA virus replication complexes. PLoS Biol. 2008 Oct 10/28/2008; 6(10): e270. PMID: 18959488, PMCID: PMC2573941, PII: 08-PLBI-P-3557, DOI: 10.1371/journal.pbio.0060270, ISSN: 1545-7885.

Sparks JS, Donaldson EF, Lu X, Baric RS, Denison MR. A novel mutation in murine hepatitis virus nsp5, the viral 3C-like proteinase, causes temperature-sensitive defects in viral growth and protein processing. J. Virol [print-electronic]. 2008 Jun; 82(12): 5999-6008. PMID: 18385240, PMCID: PMC2395152, PII: JVI.00203-08, DOI: 10.1128/JVI.00203-08, ISSN: 1098-5514.

Graham RL, Sparks JS, Eckerle LD, Sims AC, Denison MR. SARS coronavirus replicase proteins in pathogenesis. Virus Res [print-electronic]. 2008 Apr; 133(1): 88-100. PMID: 17397959, PMCID: PMC2637536, PII: S0168-1702(07)00057-3, DOI: 10.1016/j.virusres.2007.02.017, ISSN: 0168-1702.

Sparks JS, Lu X, Denison MR. Genetic analysis of Murine hepatitis virus nsp4 in virus replication. J. Virol [print-electronic]. 2007 Nov; 81(22): 12554-63. PMID: 17855548, PMCID: PMC2169011, PII: JVI.01257-07, DOI: 10.1128/JVI.01257-07, ISSN: 0022-538X.

Eckerle LD, Lu X, Sperry SM, Choi L, Denison MR. High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants. J. Virol [print-electronic]. 2007 Nov; 81(22): 12135-44. PMID: 17804504, PMCID: PMC2169014, PII: JVI.01296-07, DOI: 10.1128/JVI.01296-07, ISSN: 0022-538X.

Graham RL, Denison MR. Replication of murine hepatitis virus is regulated by papain-like proteinase 1 processing of nonstructural proteins 1, 2, and 3. J. Virol [print-electronic]. 2006 Dec; 80(23): 11610-20. PMID: 16971428, PMCID: PMC1642617, PII: JVI.01428-06, DOI: 10.1128/JVI.01428-06, ISSN: 0022-538X.

Graham RL, Sims AC, Baric RS, Denison MR. The nsp2 proteins of mouse hepatitis virus and SARS coronavirus are dispensable for viral replication. Adv. Exp. Med. Biol. 2006; 581: 67-72. PMID: 17037506, DOI: 10.1007/978-0-387-33012-9_10, ISSN: 0065-2598.

Eckerle LD, Brockway SM, Sperry SM, Lu X, Denison MR. Effects of mutagenesis of murine hepatitis virus nsp1 and nsp14 on replication in culture. Adv. Exp. Med. Biol. 2006; 581: 55-60. PMID: 17037504, DOI: 10.1007/978-0-387-33012-9_8, ISSN: 0065-2598.

Graham RL, Sims AC, Brockway SM, Baric RS, Denison MR. The nsp2 replicase proteins of murine hepatitis virus and severe acute respiratory syndrome coronavirus are dispensable for viral replication. J. Virol. 2005 Nov; 79(21): 13399-411. PMID: 16227261, PMCID: PMC1262610, PII: 79/21/13399, DOI: 10.1128/JVI.79.21.13399-13411.2005, ISSN: 0022-538X.

Brockway SM, Denison MR. Mutagenesis of the murine hepatitis virus nsp1-coding region identifies residues important for protein processing, viral RNA synthesis, and viral replication. Virology. 2005 Sep 9/30/2005; 340(2): 209-23. PMID: 16051301, PII: S0042-6822(05)00377-6, DOI: 10.1016/j.virol.2005.06.035, ISSN: 0042-6822.

Sperry SM, Kazi L, Graham RL, Baric RS, Weiss SR, Denison MR. Single-amino-acid substitutions in open reading frame (ORF) 1b-nsp14 and ORF 2a proteins of the coronavirus mouse hepatitis virus are attenuating in mice. J. Virol. 2005 Mar; 79(6): 3391-400. PMID: 15731233, PMCID: PMC1075728, PII: 79/6/3391, DOI: 10.1128/JVI.79.6.3391-3400.2005, ISSN: 0022-538X.

Denison MR. Severe acute respiratory syndrome coronavirus pathogenesis, disease and vaccines: an update. Pediatr. Infect. Dis. J. 2004 Nov; 23(11 Suppl): S207-14. PMID: 15577575, PII: 00006454-200411001-00005, ISSN: 0891-3668.

Brockway SM, Lu XT, Peters TR, Dermody TS, Denison MR. Intracellular localization and protein interactions of the gene 1 protein p28 during mouse hepatitis virus replication. J. Virol. 2004 Nov; 78(21): 11551-62. PMID: 15479796, PMCID: PMC523235, PII: 78/21/11551, DOI: 10.1128/JVI.78.21.11551-11562.2004, ISSN: 0022-538X.

Prentice E, McAuliffe J, Lu X, Subbarao K, Denison MR. Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins. J. Virol. 2004 Sep; 78(18): 9977-86. PMID: 15331731, PMCID: PMC514967, PII: 78/18/9977, DOI: 10.1128/JVI.78.18.9977-9986.2004, ISSN: 0022-538X.

Denison MR, Yount B, Brockway SM, Graham RL, Sims AC, Lu X, Baric RS. Cleavage between replicase proteins p28 and p65 of mouse hepatitis virus is not required for virus replication. J. Virol. 2004 Jun; 78(11): 5957-65. PMID: 15140993, PMCID: PMC415798, PII: 78/11/5957, DOI: 10.1128/JVI.78.11.5957-5965.2004, ISSN: 0022-538X.

Prentice E, Jerome WG, Yoshimori T, Mizushima N, Denison MR. Coronavirus replication complex formation utilizes components of cellular autophagy. J. Biol. Chem [print-electronic]. 2004 Mar 3/12/2004; 279(11): 10136-41. PMID: 14699140, PII: M306124200, DOI: 10.1074/jbc.M306124200, ISSN: 0021-9258.

Brockway SM, Clay CT, Lu XT, Denison MR. Characterization of the expression, intracellular localization, and replication complex association of the putative mouse hepatitis virus RNA-dependent RNA polymerase. J. Virol. 2003 Oct; 77(19): 10515-27. PMID: 12970436, PMCID: PMC228489, ISSN: 0022-538X.

Hostetler MA, Suara RO, Denison MR. Unilateral facial paralysis occurring in an infant with enteroviral otitis media and aseptic meningitis. J Emerg Med. 2002 Apr; 22(3): 267-71. PMID: 11932090, PII: S0736467901004838, ISSN: 0736-4679.

Bost AG, Prentice E, Denison MR. Mouse hepatitis virus replicase protein complexes are translocated to sites of M protein accumulation in the ERGIC at late times of infection. Virology. 2001 Jun 6/20/2001; 285(1): 21-9. PMID: 11414802, PII: S0042-6822(01)90932-8, DOI: 10.1006/viro.2001.0932, ISSN: 0042-6822.

Denison MR, Sims AC. MHV-A59 gene 1 proteins are associated with two distinct membrane populations. Adv. Exp. Med. Biol. 2001; 494: 655-61. PMID: 11774541, ISSN: 0065-2598.

Prentice E, Denison MR. The cell biology of coronavirus infection. Adv. Exp. Med. Biol. 2001; 494: 609-14. PMID: 11774533, ISSN: 0065-2598.

Bost AG, Prentice E, and Denison MR. Mouse hepatitis virus replicase protein complexes are translocated to sites of M protein accumulation in the ERGIC at late times of infection. Virology. 2001; 285: 21-9.

Sims AC, Ostermann J, Denison MR. Mouse hepatitis virus replicase proteins associate with two distinct populations of intracellular membranes. J. Virol. 2000 Jun; 74(12): 5647-54. PMID: 10823872, PMCID: PMC112052, ISSN: 0022-538X.

Bost AG, Carnahan RH, Lu XT, Denison MR. Four proteins processed from the replicase gene polyprotein of mouse hepatitis virus colocalize in the cell periphery and adjacent to sites of virion assembly. J. Virol. 2000 Apr; 74(7): 3379-87. PMID: 10708455, PMCID: PMC111839, ISSN: 0022-538X.

Bost AG; Carnahan RH; Lu XT; Denison MR. Four proteins processed from the replicase gene polyprotein of mouse hepatitis virus colocalize in the cell periphery and adjacent to sites of virion assembly. J. Virol. 2000; 74((7)): 3379-87.

Sims AC, Ostermann J, and Denison MR. Mouse hepatitis virus gene 1 proteins associate with distinct intracellular membranes. J. Virol. 2000; 74: 5647-54.

Denison MR, Spaan WJ, van der Meer Y, Gibson CA, Sims AC, Prentice E, Lu XT. The putative helicase of the coronavirus mouse hepatitis virus is processed from the replicase gene polyprotein and localizes in complexes that are active in viral RNA synthesis. J. Virol. 1999 Aug; 73(8): 6862-71. PMID: 10400784, PMCID: PMC112771, ISSN: 0022-538X.

Denison MR, Spaan WJ, van der Meer Y, Gibson CA, Sims AC, Prentice E, Lu XT. The putative helicase of the coronavirus mouse hepatitis virus is processed from the replicase gene polyprotein and localized in complexes that are active in viral RNA synthesis. J. Virol. 1999; (8)((73)): 6862-71.

van der Meer Y, Snijder EJ, Dobbe JC, Schleich S, Denison MR, Spaan WJM, and Krijnse-Locker J. Localization of mouse hepatitis virus nonstructural proteins and RNA synthesis indicates a role for late endosomes in viral replication. J Virol. 1999; 73((9)): 7641-57.

Lu XT, Sims AC, Denison MR. Mouse hepatitis virus 3C-like protease cleaves a 22-kilodalton protein from the open reading frame 1a polyprotein in virus-infected cells and in vitro. J. Virol. 1998 Mar; 72(3): 2265-71. PMID: 9499085, PMCID: PMC109524, ISSN: 0022-538X.

Gibson CA, Chen J, Monroe SA, Denison MR. Expression and processing of nonstructural proteins of the human astroviruses. Adv. Exp. Med. Biol. 1998; 440: 387-91. PMID: 9782307, ISSN: 0065-2598.

Sims AC, Lu XT, Denison MR. Expression, purification, and activity of recombinant MHV-A59 3CLpro. Adv. Exp. Med. Biol. 1998; 440: 129-34. PMID: 9782274, ISSN: 0065-2598.

Denison MR, Sims AC, Gibson CA, Lu XT. Processing of the MHV-A59 gene 1 polyprotein by the 3C-like proteinase. Adv. Exp. Med. Biol. 1998; 440: 121-7. PMID: 9782273, ISSN: 0065-2598.

Lu, XT, Sims AC, and Denison MR. Mouse hepatitis virus 3C-Like protease cleaves a 22 -Kilodalton protein from the open reading frame 1a polyprotein in virus-infected cells and in vitro. J Virol. 1998; 72((3)): 2265-71.

Gibson CA and Denison MR. Coronavirus picornain-like cysteine proteinase. Handbook of Proteolytic Enzymes. 1998; 726-9.

Sims AC, Lu XT, and Denison MR. Expression, purification and activity of recombinant MHV-A59 3CLpro. Advances in Experimental Medicine and Biology. 1998; 440: 129-34.

Lu Y, Denison MR. Determinants of mouse hepatitis virus 3C-like proteinase activity. Virology. 1997 Apr 4/14/1997; 230(2): 335-42. PMID: 9143289, PII: S0042-6822(97)98479-8, DOI: 10.1006/viro.1997.8479, ISSN: 0042-6822.

Lu, YQ and Denison MR. Determinants of mouse hepatitis virus 3C-like proteinase activity. Virology. 1997; 230: 335-42.

Fisher RG, Denison MR. Veillonella parvula bacteremia without an underlying source. J. Clin. Microbiol. 1996 Dec; 34(12): 3235-6. PMID: 8940482, PMCID: PMC229493, ISSN: 0095-1137.

Lu X, Lu Y, Denison MR. Intracellular and in vitro-translated 27-kDa proteins contain the 3C-like proteinase activity of the coronavirus MHV-A59. Virology. 1996 Aug 8/15/1996; 222(2): 375-82. PMID: 8806521, PII: S0042-6822(96)90434-1, DOI: 10.1006/viro.1996.0434, ISSN: 0042-6822.

Kolquist KA, Vnencak-Jones CL, Swift L, Page DL, Johnson JE, Denison MR. Fatal fat embolism syndrome in a child with undiagnosed hemoglobin S/beta+ thalassemia: a complication of acute parvovirus B19 infection. Pediatr Pathol Lab Med. 1996 Jan; 16(1): 71-82. PMID: 8963632, ISSN: 1077-1042.

Lu XT, Lu YQ, and Denison, MR. Intracellular and in vitro translated 27 kDa proteins contain the 3C-like proteinase activity of the coronavirus MHV-A59. Virology. 1996; 222: 375-82.

Lu Y, Lu X, Denison MR. Identification and characterization of a serine-like proteinase of the murine coronavirus MHV-A59. J. Virol. 1995 Jun; 69(6): 3554-9. PMID: 7745703, PMCID: PMC189070, ISSN: 0022-538X.

Kim JC, Spence RA, Currier PF, Lu X, Denison MR. Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d. Virology. 1995 Apr 4/1/1995; 208(1): 1-8. PMID: 11831690, PII: S0042-6822(85)71123-3, DOI: 10.1006/viro.1995.1123, ISSN: 0042-6822.

Denison MR, Hughes SA, Weiss SR. Identification and characterization of a 65-kDa protein processed from the gene 1 polyprotein of the murine coronavirus MHV-A59. Virology. 1995 Feb 2/20/1995; 207(1): 316-20. PMID: 7871746, PII: S0042-6822(85)71085-9, DOI: 10.1006/viro.1995.1085, ISSN: 0042-6822.

Denison MR, Kim JC, Ross T. Inhibition of coronavirus MHV-A59 replication by proteinase inhibitors. Adv. Exp. Med. Biol. 1995; 380: 391-7. PMID: 8830514, ISSN: 0065-2598.

Kim JC, Spence RA, Currier PF, Lu X and Denison MR. Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d. Virology. 1995; 208: 1-8.

Lu YQ, Lu XT, and Denison MR. Identification and characterization of a serine-like proteinase of the murine coronavirus MHV-A59. Journal of Virology. 1995; 69((6)): 3554-9.

Denison MR, Hughes SA, and Weiss SR. Identification and characterization of a 65 kilodalton protein processed from the gene 1 polyprotein of the murine coronavirus MHV- A59. Virology. 1995; 207((1)): 316-20.

Denison MR. Viral Pharyngitis. Seminars in Pediatric Infectious Diseases. 1995; 6((2)): 62-8.

Weiss SR, Hughes SA, Bonilla PJ, Turner JD, Leibowitz JL, and Denison MR. Coronavirus polyprotein processing. Archives of Virology. 1994; 9((suppl)): 349-58.

Hughes, S. A., M. R. Denison, P. Bonilla, J. L. Leibowitz, R. S. Baric and S. R. Weiss. A newly identified MHV-A59 ORF1a polypeptide p65 is temperature sensitive in two RNA negative mutants. Advances in Experimental Medicine & Biology. 1993; 342: 221-6.

Denison, M.R., Zoltick, P.W., Hughes, S.A., Giangreco, B., Olson, A.L., Perlman, S., Leibowitz, J.L., and Weiss, S.R. Intracellular processing of the N-terminal ORF la proteins of the coronavirus MHV-A59 requires multiple proteolytic events. Virology. 1992; 189: 274-84.

Denison M.R., Zoltick, P.W., Leibowitz, J.L., Pachuk, C.J., and Weiss, S.R. Identification of polypeptides encoded in ORF la of the putative polymerase gene of the murine coronavirus MHV-A59. J. Virology. 1991; 65: 3706-82.

Denison, M.R., and Perlman, S. Identification of Putative Polymerase Gene Product in Cells Infected with Mouse Murine Coronavirus A59. Virology. 1987; 157: 565-8.

Denison MR and Perlman S. Translation and processing of MHV-A59 virion RNA in reticulocyte lysates and infected cells. Coronaviruses. 1987; 155.

Denison, M.R., and Perlman, S. Translation and Processing of Mouse Hepatitis Virus Virion RNA in a Cell-Free System. J. Virol. 1986; 60((1)): 12-8.

Turner, BJ, Denison MR, Eppes SC, Houchens R, Fanning T, and Markson LE. Survival experience of 789 children with the acquired immunodeficiency syndrome. Pediatric Infectious Disease Journal. 12: 310-20.

Denison MR, Kim JC, and Ross T. Inhibitor of coronavirus MHV-A59 replication by proteinase inhibitors. Coronaviruses.

Denison MR, Sims AC, Gibson CA, and Lu XT. Processing of the MHV-A59 gene 1 polyprotein by the 3C-like proteinase. Advances in Experimental Medicine and Biology. 440: 121-8.

Gibson CA, Chen J, Monroe SA, and Denison MR. Expression and processing of the nonstructural proteins of the human astroviruses. Advances in Experimental Medicine and Biology. 440: 387-94.

Available Postdoctoral Position Details
Posted: 8/13/2019

The Denison Laboratory studies coronaviruses (CoVs), a family of plus-strand RNA viruses that comprise a variety of human and animal pathogens. Human disease ranges from mild common colds caused by widely circulating endemic CoV strains to severe and frequently fatal respiratory disease from zoonotic CoVs such as those responsible for severe acute respiratory syndrome (SARS) and Middle-East respiratory syndrome (MERS). We use integrated virologic, biochemical, and genetic approaches for studies of MERS-CoV, SARS-CoV, and the model coronavirus, mouse hepatitis virus (MHV), to understand the replication, cell biology, and protein functions of CoVs. We further apply this knowledge to development of preventive and therapeutic countermeasures against emerging CoV infections. We are looking for an enthusiastic postdoctoral fellow to drive forward a research project focused on defining the role of viral replication fidelity in the regulation of CoV fitness, evolution, and pathogenesis. Qualifications: PhD in microbiology, molecular biology, cell biology, biochemistry, or related field required. Virology experience preferred. To apply, please email your CV and cover letter to Andrea Pruijssers: ardina.pruijssers@vumc.org.