Biomedical Research Education & Training
Faculty Member

Denison, Mark R., M.D.
Professor of Pediatrics
Professor of Pathology, Microbiology and Immunology
Craig-Weaver Chair in Pediatics

Lab Url: N/A

Phone Number: 615-343-9881

Email Address: mark.denison@vanderbilt.edu

Denison, Mark's picture
Academic history
B.A., University of Kansas, Lawrence KS
M.D., University of Kansas Medical School, Ks. City, KS
Fellowship, University of Iowa Hospitals, Iowa CIty, IA
Residency, University of Iowa Hospitals, Iowa CIty, IA

Office Address   Mailing Address

D-6217 Medical Center North

D-6217 MCN Vanderbilt University Medical Center 37232-2581


Research Keywords
Coronavirus, SARS, mouse hepatitis virus, replication, genetics, antivirals, vaccines,Infectious disease,Membrane,Microbiology,Protein Structure,Proteomics,Virus

Research Specialty
Coronavirus / SARS replication Virus cell biology Emerging viruses in biodefense Synthetic biology

Research Description
The Denison Lab studies the coronaviruses, a family of plus-strand RNA viruses that cause important infections in many animals and colds in humans. A new coronavirus recently has been identified as the cause of severe acute respiratory syndrome (SARS). The Denison laboratory studies the model coronavirus, mouse hepatitis virus (MHV) to understand the replication, cell biology, and protein functions of coronaviruses. The laboratory uses biochemical and genetic approaches, including the recent introduction of reverse genetic approaches, to define the specific functions of replicase proteins in the formation and function of viral replication complexes. In addition, the laboratory has a program to define the replication of the SARS coronavirus (SARS-CoV) and develop virus mutants as live virus vaccine candidates. The Denison laboratory has an active training program for students and postdoctoral fellows to develop new investigators in viral cell biology, molecular biology, and genetics. .

Publications
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, 50(11), 1493-6, 2010 PMCID:2865531

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, 6(5), e1000896, 2010 PMCID:2865531

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, 2010 PMCID:2865531

Gadlage, MJ, Denison, MR. Exchange of the coronavirus replicase polyprotein cleavage sites alters protease specificity and processing. J Virol, 84(13), 6894-8, 2010 PMCID:2865531

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, 84(1), 280-90, 2010 PMCID:2798404

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, 105(50), 19944-9, 2008 PMCID:2588415

Denison, MR. Seeking membranes: positive-strand RNA virus replication complexes. PLoS Biol, 6(10), e270, 2008 PMCID:2573941

Gadlage, MJ, Graham, RL, Denison, MR. Murine coronaviruses encoding nsp2 at different genomic loci have altered replication, protein expression, and localization. J Virol, 82(23), 11964-9, 2008 PMCID:2583644

Graham, RL, Sparks, JS, Eckerle, LD, Sims, AC, Denison, MR. SARS coronavirus replicase proteins in pathogenesis. Virus Res, 133(1), 88-100, 2008 PMCID:2637536

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, 82(12), 5999-6008, 2008 PMCID:2395152

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, 81(22), 12135-44, 2007 PMCID:2169014

Sparks, JS, Lu, X, Denison, MR. Genetic analysis of Murine hepatitis virus nsp4 in virus replication. J Virol, 81(22), 12554-63, 2007 PMCID:2169011

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, 581, 55-60, 2006

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, 80(23), 11610-20, 2006 PMCID:1642617

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, 581, 67-72, 2006

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, 340(2), 209-23, 2005

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, 79(21), 13399-411, 2005 PMCID:1262610

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, 79(6), 3391-400, 2005 PMCID:1075728

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, 78(21), 11551-62, 2004 PMCID:523235

Denison, MR. Severe acute respiratory syndrome coronavirus pathogenesis, disease and vaccines: an update. Pediatr Infect Dis J, 23(11 Suppl), S207-14, 2004

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, 78(11), 5957-65, 2004 PMCID:415798

Prentice, E, Jerome, WG, Yoshimori, T, Mizushima, N, Denison, MR. Coronavirus replication complex formation utilizes components of cellular autophagy. J Biol Chem, 279(11), 10136-41, 2004

Prentice, E, McAuliffe, J, Lu, X, Subbarao, K, Denison, MR. Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins. J Virol, 78(18), 9977-86, 2004 PMCID:514967

Brockway, Sarah M, Clay, Corrie T, Lu, Xiao Tao, Denison, Mark R. Characterization of the expression, intracellular localization, and replication complex association of the putative mouse hepatitis virus RNA-dependent RNA polymerase. J Virol, 77(19), 10515-27, 2003 PMCID:228489

Hostetler, Mark A, Suara, Rahaman O, Denison, Mark R. Unilateral facial paralysis occurring in an infant with enteroviral otitis media and aseptic meningitis. J Emerg Med, 22(3), 267-71, 2002

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, 285, 21-29, 2001

Bost, A G, Prentice, E, Denison, M R. Mouse hepatitis virus replicase protein complexes are translocated to sites of M protein accumulation in the ERGIC at late times of infection. Virology, 285(1), 21-9, 2001

Denison, M R, Sims, A C. MHV-A59 gene 1 proteins are associated with two distinct membrane populations. Adv Exp Med Biol, 494, 655-61, 2001

Prentice, E, Denison, M R. The cell biology of coronavirus infection. Adv Exp Med Biol, 494, 609-14, 2001

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., 74(7), 3379-87, 2000

Bost, A G, Carnahan, R H, Lu, X T, Denison, M R. 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, 74(7), 3379-87, 2000 PMCID:111839

Sims AC, Ostermann J, and Denison MR. Mouse hepatitis virus gene 1 proteins associate with distinct intracellular membranes. J. Virol, 74, 5647-5654, 2000

Sims, A C, Ostermann, J, Denison, M R. Mouse hepatitis virus replicase proteins associate with two distinct populations of intracellular membranes. J Virol, 74(12), 5647-54, 2000 PMCID:112052

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., (8)(73), 6862-71, 1999

Denison, M R, Spaan, W J, van der Meer, Y, Gibson, C A, Sims, A C, Prentice, E, Lu, X T. 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, 73(8), 6862-71, 1999 PMCID:112771

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, 73(9), 7641-7657, 1999

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, 121-128, 1998.

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, 387-394, 1998.

Denison, M R, Sims, A C, Gibson, C A, Lu, X T. Processing of the MHV-A59 gene 1 polyprotein by the 3C-like proteinase. Adv Exp Med Biol, 440, 121-7, 1998

Gibson CA and Denison MR. Coronavirus picornain-like cysteine proteinase. Handbook of Proteolytic Enzymes, 726-729, 1998

Gibson, C A, Chen, J, Monroe, S A, Denison, M R. Expression and processing of nonstructural proteins of the human astroviruses. Adv Exp Med Biol, 440, 387-91, 1998

Lu, X T, Sims, A C, Denison, M R. 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, 72(3), 2265-71, 1998 PMCID:109524

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, 72(3), 2265-2271, 1998

Sims AC, Lu XT, and Denison MR. Expression, purification and activity of recombinant MHV-A59 3CLpro. Advances in Experimental Medicine and Biology, 440, 129-134, 1998

Sims, A C, Lu, X T, Denison, M R. Expression, purification, and activity of recombinant MHV-A59 3CLpro. Adv Exp Med Biol, 440, 129-34, 1998

Lu, Y, Denison, M R. Determinants of mouse hepatitis virus 3C-like proteinase activity. Virology, 230(2), 335-42, 1997

Lu, YQ and Denison MR. Determinants of mouse hepatitis virus 3C-like proteinase activity. Virology , 230, 335-342, 1997

Fisher, R G, Denison, M R. Veillonella parvula bacteremia without an underlying source. J Clin Microbiol, 34(12), 3235-6, 1996 PMCID:229493

Kolquist, K A, Vnencak-Jones, C L, Swift, L, Page, D L, Johnson, J E, Denison, M R. Fatal fat embolism syndrome in a child with undiagnosed hemoglobin S/beta+ thalassemia: a complication of acute parvovirus B19 infection. Pediatr Pathol Lab Med, 16(1), 71-82, 1996

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 , 222, 375-382, 1996

Lu, X, Lu, Y, Denison, M R. Intracellular and in vitro-translated 27-kDa proteins contain the 3C-like proteinase activity of the coronavirus MHV-A59. Virology, 222(2), 375-82, 1996

Denison MR, Kim JC, and Ross T. Inhibitor of coronavirus MHV-A59 replication by proteinase inhibitors. Coronaviruses, 1995.

Denison MR. Viral Pharyngitis. Seminars in Pediatric Infectious Diseases, 6(2), 62-68, 1995

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, 207(1), 316-320, 1995

Denison, M R, Hughes, S A, Weiss, S R. Identification and characterization of a 65-kDa protein processed from the gene 1 polyprotein of the murine coronavirus MHV-A59. Virology, 207(1), 316-20, 1995

Denison, M R, Kim, J C, Ross, T. Inhibition of coronavirus MHV-A59 replication by proteinase inhibitors. Adv Exp Med Biol, 380, 391-7, 1995

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 , 208, 1-8, 1995

Kim, J C, Spence, R A, Currier, P F, Lu, X, Denison, M R. Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d. Virology, 208(1), 1-8, 1995

Lu YQ, Lu XT, and Denison MR. Identification and characterization of a serine-like proteinase of the murine coronavirus MHV-A59. Journal of Virology , 69(6), 3554-3559, 1995

Lu, Y, Lu, X, Denison, M R. Identification and characterization of a serine-like proteinase of the murine coronavirus MHV-A59. J Virol, 69(6), 3554-9, 1995 PMCID:189070

Weiss SR, Hughes SA, Bonilla PJ, Turner JD, Leibowitz JL, and Denison MR. Coronavirus polyprotein processing. Archives of Virology, 9(suppl), 349-358, 1994

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, 1993.

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, 342, 221-6, 1993

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, 189, 274-284, 1992

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, 65, 3706-3782, 1991

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

Denison, M.R., and Perlman, S. Identification of Putative Polymerase Gene Product in Cells Infected with Mouse Murine Coronavirus A59. Virology , 157, 565-568, 1987

Denison, M.R., and Perlman, S. Translation and Processing of Mouse Hepatitis Virus Virion RNA in a Cell-Free System. J. Virol., 60(1), 12-18, 1986


Postdoctoral Position Available
Yes

Postdoctoral Position Details
Our lab studies the replication, pathogenesis, cell biology and evolution of Coronaviruses, a family of RNA viruses from which human SARS-CoV and MERS-CoV emerged to cause worldwide epidemics. CoVs encode many novel functions in the largest known RNA genomes, including novel nsp5 protease and an unprecedented proofreading exoribonuclease (ExoN) in nsp14. Thus CoVs are a model for understanding mechanisms of virus evolution, replication and host species movement.

Postdoctoral positions are available to understand basic mechanisms of CoV replication, cell biology, pathogenesis and evolution, and to identify novel targets for attenuation and inhibition of CoV replication and disease. Projects in the lab use the BSL2 model virus murine hepatitis virus (MHV) as well as the SARS-CoV and MERS-CoV. Current available projects in the lab include
1) CoV nsp5 protease structure / function during coronavirus replication; 2) Role of the CoV nsp15 endoribonuclease in CoV replication fidelity and RNA synthesis; 3) Superresolution imaging of coronavirus replication complex formation 4) Determinants of CoV replication fidelity; and 5) Inhibitors of CoV fidelity and capping

Updated Date
11/20/2013