Mark R. Denison, M.D.

Professor

mark.denison@vanderbilt.edu
Faculty Appointments
Professor of Pediatrics Craig-Weaver Chair in PediaticsProfessor of Pathology, Microbiology and Immunology
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 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. .
Research Keywords
Coronavirus / SARS replication Virus cell biology Emerging viruses in biodefense Synthetic biology
Publications
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
Postdoctoral Positions are available to study the replication, cell biology and vaccine development for coronaviruses, using the model coronavirus mouse hepatitis virus (MHV) and the recently emerged SARS coronavirus (SARS-CoV). Positions are available to study: 1) The replicase protein functions of mouse hepatitis virus; 2) Virus-cell interactions and replication complex formation and function of MHV; 3) Replicase protein expression, processing and functions of SARS-CoV; 4) Reverse genetic analysis of SARS-CoV replicase proteins and development of attenuated mutant viruses;