MICHAEL A. WHITT, Ph.D., B.A.

Professor and Interim Chair
Dept. of Microbiology, Immunology & Biochemistry

Office: 601c Molecular Sciences Building
Tel: (901) 448-4634
mwhitt@uthsc.edu

Education

  • PostDoc, Yale University School of Medicine, Virology/Cell Biology
  • Ph.D., University of California, Davis, CA, Microbiology
  • B.A., University of Kansas, Lawrence, KS, Microbiology

Research description

My laboratory studies a prototypic nonsegmented negative-strand RNA virus called vesicular stomatitis virus (VSV). One of the long-term goals of our studies is to develop novel viral therapeutic agents based on recombinant viruses derived from VSV replicons. My lab was one of the first in 1995 to develop a "reverse genetics" system for VSV, which has formed the foundation for all of our current work. We have used this system extensively to understand basic aspects of VSV biology and have applied the knowledge gained from these studies to develop cell-specific targeting and oncolytic vectors.  I currently hold two patents for this technology.  Our current research efforts have focused on developing VSV as an oncolytic vector for glioblastoma multiforme and have initiated studies to develop vectors to target melanoma.

In addition to our translational work developing oncolytic VSV vectors, we continue to dissect functional domains in the envelope glycoprotein (G) of VSV.  Recently we found that VSV-G has an low-pH induced ion channel activity that appears to contribute to virus infectivity and may also be important for virus assembly and budding.  Through a collaboration with Dr. John Cox at UTHSC, we have been using GFP and Ds-Red fusion of VSV-G to study the effect of alternative cytoplasmic domain on the intracellular trafficking of protein cargo through the secretory pathway.  Using this approach we have identified a novel sorting pathway through the Golgi that is Arf1-independent and instead involves a newly identify, small GTP binding protein, Rab43.  Our immediate goal is to identify other host factors that are required for transport of proteins through this novel pathway and the understand how cytoplasmic domain sequences are recognized by the cellular sorting machinery as they are transported to their ultimate destination within cells.

Research interest/specialty

My expertise is molecular virology, with an emphasis on virus entry, assembly and cytopathogenesis. I also have extensive cell biology and molecular biology experience. I currently serve as Interim Chair of our department, and serve on numerous other University-wide committees.

Research keywords

Negative-strand RNA virus entry, replication and assembly. Vesicular Stomatitis Virus (VSV) biology. Development of VSV-based, cell-specific therapeutic and oncolytic vectors. Confocal microscopy.

Area of teaching/subject

Virology, Molecular Techniques, Immune response to cancer

Publications

  1. Du, Z, Whitt, MA, Baumann, J, Garner, JM, Morton, CL, Davidoff, AM, Pfeffer, LM. Inhibition of type I interferon-mediated antiviral action in human glioma cells by the IKK inhibitors BMS-345541 and TPCA-1. J Interferon Cytokine Res, 32 (8), 368-77, 2012.
  2. Whitt, MA, Mire, CE. Utilization of fluorescently-labeled tetracysteine-tagged proteins to study virus entry by live cell microscopy. Methods, 55 (2), 127-36, 2011.
  3. Mire, CE, Whitt, MA. The protease-sensitive loop of the vesicular stomatitis virus matrix protein is involved in virus assembly and protein translation. Virology, 416 (1-2), 16-25, 2011.
  4. Whitt, MA. Generation of VSV pseudotypes using recombinant ΔG-VSV for studies on virus entry, identification of entry inhibitors, and immune responses to vaccines. J Virol Methods, 169 (2), 365-74, 2010.
  5. Chang, G, Xu, S, Watanabe, M, Jayakar, HR, Whitt, MA, Gingrich, JR. Enhanced Oncolytic Activity of Vesicular Stomatitis Virus Encoding SV5-F Protein Against Prostate Cancer. J Urol, 2010.
  6. Mire, CE, White, JM, Whitt, MA. A spatio-temporal analysis of matrix protein and nucleocapsid trafficking during vesicular stomatitis virus uncoating. PLoS Pathog, 6 (7), e1000994, 2010.
  7. Mire, CE, Dube, D, Delos, SE, White, JM, Whitt, MA. Glycoprotein-dependent acidification of vesicular stomatitis virus enhances release of matrix protein. J Virol, 83 (23), 12139-50, 2009.
  8. Clinton, SR, Bina, JE, Hatch, TP, Whitt, MA, Miller, MA. Binding and activation of host plasminogen on the surface of Francisella tularensis. BMC Microbiol, 10, 76, 2009.
  9. Porotto, M, Orefice, G, Yokoyama, C, Mungall, B, Realubit, R, Sganga, M, Aljofan, M, Whitt, M, Glickman, F, Moscona, A. Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy. J Virol, 2009.
  10. Lavine, CL, Clinton, SR, Angelova-Fischer, I, Marion, TN, Bina, XR, Bina, JE, Whitt, MA, Miller, MA. Immunization with heat-killed Francisella tularensis LVS elicits protective antibody-mediated immunity. Eur J Immunol, 37 (11), 3007-20, 2007.
  11. Porotto, M, Carta, P, Deng, Y, Kellogg, GE, Whitt, M, Lu, M, Mungall, BA, Moscona, A. Molecular determinants of antiviral potency of paramyxovirus entry inhibitors. J Virol, 81 (19), 10567-74, 2007.
  12. Dorsey, FC, Muthusamy, T, Whitt, MA, Cox, JV. A novel role for a YXXPhi motif in directing the caveolin-dependent sorting of membrane-spanning proteins. J Cell Sci, 120 (Pt 15), 2544-54, 2007.
  13. Tani, H, Komoda, Y, Matsuo, E, Suzuki, K, Hamamoto, I, Yamashita, T, Moriishi, K, Fujiyama, K, Kanto, T, Hayashi, N, Owsianka, A, Patel, AH, Whitt, MA, Matsuura, Y. Replication-competent recombinant vesicular stomatitis virus encoding hepatitis C virus envelope proteins. J Virol, 81 (16), 8601-12, 2007.
  14. Perez, M, Clemente, R, Robison, CS, Jeetendra, E, Jayakar, HR, Whitt, MA, de la Torre, JC. Generation and characterization of a recombinant vesicular stomatitis virus expressing the glycoprotein of Borna disease virus. J Virol, 81 (11), 5527-36, 2007.
  15. Klas, SD, Lavine, CL, Whitt, MA, Miller, MA. IL-12-assisted immunization against Listeria monocytogenes using replication-restricted VSV-based vectors. Vaccine, 24 (9), 1451-61, 2006.
  16. Wilkins, C, Dishongh, R, Moore, SC, Whitt, MA, Chow, M, Machaca, K. RNA interference is an antiviral defence mechanism in Caenorhabditis elegans. Nature, 436 (7053), 1044-7, 2005.
  17. Jayakar, HR, Jeetendra, E, Whitt, MA. Rhabdovirus assembly and budding. Virus Res, 106 (2), 117-32, 2004.
  18. Pinschewer, DD, Perez, M, Jeetendra, E, Bächi, T, Horvath, E, Hengartner, H, Whitt, MA, de la Torre, JC, Zinkernagel, RM. Kinetics of protective antibodies are determined by the viral surface antigen. J Clin Invest, 114 (7), 988-93, 2004.
  19. Irie, T, Licata, JM, Jayakar, HR, Whitt, MA, Bell, P, Harty, RN. Functional analysis of late-budding domain activity associated with the PSAP motif within the vesicular stomatitis virus M protein. J Virol, 78 (14), 7823-7, 2004.
  20. Duntsch, CD, Zhou, Q, Jayakar, HR, Weimar, JD, Robertson, JH, Pfeffer, LM, Wang, L, Xiang, Z, Whitt, MA. Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model. J Neurosurg, 100 (6), 1049-59, 2004.
  21. Gardner, LA, Delos Santos, NM, Matta, SG, Whitt, MA, Bahouth, SW. Role of the cyclic AMP-dependent protein kinase in homologous resensitization of the beta1-adrenergic receptor. J Biol Chem, 279 (20), 21135-43, 2004.
  22. Miller, MA, Lavine, CL, Klas, SD, Pfeffer, LM, Whitt, MA. Recombinant replication-restricted VSV as an expression vector for murine cytokines. Protein Expr Purif, 33 (1), 92-103, 2004.
  23. Jeetendra, E, Ghosh, K, Odell, D, Li, J, Ghosh, HP, Whitt, MA. The membrane-proximal region of vesicular stomatitis virus glycoprotein G ectodomain is critical for fusion and virus infectivity. J Virol, 77 (23), 12807-18, 2003.
  24. Klas, SD, Robison, CS, Whitt, MA, Miller, MA. Adjuvanticity of an IL-12 fusion protein expressed by recombinant deltaG-vesicular stomatitis virus. Cell Immunol, 218 (1-2), 59-73, 2002.
  25. Jeetendra, E, Robison, CS, Albritton, LM, Whitt, MA. The membrane-proximal domain of vesicular stomatitis virus G protein functions as a membrane fusion potentiator and can induce hemifusion. J Virol, 76 (23), 12300-11, 2002.
  26. Neumann, G, Whitt, MA, Kawaoka, Y. A decade after the generation of a negative-sense RNA virus from cloned cDNA - what have we learned. J Gen Virol, 83 (Pt 11), 2635-62, 2002.
  27. Jayakar, HR, Whitt, MA. Identification of two additional translation products from the matrix (M) gene that contribute to vesicular stomatitis virus cytopathology. J Virol, 76 (16), 8011-8, 2002.
  28. Harty, RN, Brown, ME, McGettigan, JP, Wang, G, Jayakar, HR, Huibregtse, JM, Whitt, MA, Schnell, MJ. Rhabdoviruses and the cellular ubiquitin-proteasome system: a budding interaction. J Virol, 75 (22), 10623-9, 2001.
  29. He, Y, Chipman, PR, Howitt, J, Bator, CM, Whitt, MA, Baker, TS, Kuhn, RJ, Anderson, CW, Freimuth, P, Rossmann, MG. Interaction of coxsackievirus B3 with the full length coxsackievirus-adenovirus receptor. Nat Struct Biol, 8 (10), 874-8, 2001.
  30. Perez, M, Watanabe, M, Whitt, MA, de la Torre, JC. N-terminal domain of Borna disease virus G (p56) protein is sufficient for virus receptor recognition and cell entry. J Virol, 75 (15), 7078-85, 2001.
  31. Matsuura, Y, Tani, H, Suzuki, K, Kimura-Someya, T, Suzuki, R, Aizaki, H, Ishii, K, Moriishi, K, Robison, CS, Whitt, MA, Miyamura, T. Characterization of pseudotype VSV possessing HCV envelope proteins. Virology, 286 (2), 263-75, 2001.
  32. Whitt, M, Buonocore, L, Rose, JK. Liposome-mediated transfection. Curr Protoc Immunol, Chapter 10, Unit 10.16, 2001.
  33. Jayakar, HR, Murti, KG, Whitt, MA. Mutations in the PPPY motif of vesicular stomatitis virus matrix protein reduce virus budding by inhibiting a late step in virion release. J Virol, 74 (21), 9818-27, 2000.
  34. Robison, CS, Whitt, MA. The membrane-proximal stem region of vesicular stomatitis virus G protein confers efficient virus assembly. J Virol, 74 (5), 2239-46, 2000.
  35. Ito, H, Watanabe, S, Sanchez, A, Whitt, MA, Kawaoka, Y. Mutational analysis of the putative fusion domain of Ebola virus glycoprotein. J Virol, 73 (10), 8907-12, 1999.
  36. Stillman, EA, Whitt, MA. Transcript initiation and 5'-end modifications are separable events during vesicular stomatitis virus transcription. J Virol, 73 (9), 7199-209, 1999.
  37. Stillman, EA, Whitt, MA. The length and sequence composition of vesicular stomatitis virus intergenic regions affect mRNA levels and the site of transcript initiation. J Virol, 72 (7), 5565-72, 1998.
  38. Fredericksen, BL, Whitt, MA. Attenuation of recombinant vesicular stomatitis viruses encoding mutant glycoproteins demonstrate a critical role for maintaining a high pH threshold for membrane fusion in viral fitness. Virology, 240 (2), 349-58, 1998.
  39. Takada, A, Robison, C, Goto, H, Sanchez, A, Murti, KG, Whitt, MA, Kawaoka, Y. A system for functional analysis of Ebola virus glycoprotein. Proc Natl Acad Sci U S A, 94 (26), 14764-9, 1997.
  40. Stillman, EA, Whitt, MA. Mutational analyses of the intergenic dinucleotide and the transcriptional start sequence of vesicular stomatitis virus (VSV) define sequences required for efficient termination and initiation of VSV transcripts. J Virol, 71 (3), 2127-37, 1997.
  41. Schnell, MJ, Buonocore, L, Whitt, MA, Rose, JK. The minimal conserved transcription stop-start signal promotes stable expression of a foreign gene in vesicular stomatitis virus. J Virol, 70 (4), 2318-23, 1996.
  42. Fredericksen, BL, Whitt, MA. Mutations at two conserved acidic amino acids in the glycoprotein of vesicular stomatitis virus affect pH-dependent conformational changes and reduce the pH threshold for membrane fusion. Virology, 217 (1), 49-57, 1996.
  43. Kretzschmar, E, Peluso, R, Schnell, MJ, Whitt, MA, Rose, JK. Normal replication of vesicular stomatitis virus without C proteins. Virology, 216 (2), 309-16, 1996.
  44. Yang, Y, Vanin, EF, Whitt, MA, Fornerod, M, Zwart, R, Schneiderman, RD, Grosveld, G, Nienhuis, AW. Inducible, high-level production of infectious murine leukemia retroviral vector particles pseudotyped with vesicular stomatitis virus G envelope protein. Hum Gene Ther, 6 (9), 1203-13, 1995.
  45. Lawson, ND, Stillman, EA, Whitt, MA, Rose, JK. Recombinant vesicular stomatitis viruses from DNA. Proc Natl Acad Sci U S A, 92 (10), 4477-81, 1995.
  46. Stillman, EA, Rose, JK, Whitt, MA. Replication and amplification of novel vesicular stomatitis virus minigenomes encoding viral structural proteins. J Virol, 69 (5), 2946-53, 1995.
  47. Fredericksen, BL, Whitt, MA. Vesicular stomatitis virus glycoprotein mutations that affect membrane fusion activity and abolish virus infectivity. J Virol, 69 (3), 1435-43, 1995.
  48. Whitt, MA, Buonocore, L, Prehaud, C, Rose, JK. Membrane fusion activity, oligomerization, and assembly of the rabies virus glycoprotein. Virology, 185 (2), 681-8, 1991.
  49. Whitt, MA, Rose, JK. Fatty acid acylation is not required for membrane fusion activity or glycoprotein assembly into VSV virions. Virology, 185 (2), 875-8, 1991.
  50. Rose, JK, Buonocore, L, Whitt, MA. A new cationic liposome reagent mediating nearly quantitative transfection of animal cells. Biotechniques, 10 (4), 520-5, 1991.
  51. Whitt, MA, Zagouras, P, Crise, B, Rose, JK. A fusion-defective mutant of the vesicular stomatitis virus glycoprotein. J Virol, 64 (10), 4907-13, 1990.
  52. Whitt, MA, Chong, L, Rose, JK. Glycoprotein cytoplasmic domain sequences required for rescue of a vesicular stomatitis virus glycoprotein mutant. J Virol, 63 (9), 3569-78, 1989.
  53. Whitt, MA, Manning, JS. A phosphorylated 34-kDa protein and a subpopulation of polyhedrin are thiol linked to the carbohydrate layer surrounding a baculovirus occlusion body. Virology, 163 (1), 33-42, 1988.