Faculty A-Z

Thomas I. Michalak

Honorary Research Professor Professor of Molecular Virology and Medicine (Hepatology) Canada Research Chair (Tier 1) in Molecular Virology M.D. Ph.D. Warsaw

Lab Medicine

Phone:
709-864-3338

Email:
timich@mun.ca

Address:
Molecular Virology and Hepatology Research Group Faculty of Medicine Health Sciences Centre Memorial University 300 Prince Philip Drive St. John’s, NL Canada A1B 3V6


Links: Canada Research Chairs page
PubMed

MOLECULAR PATHOGENESIS AND IMMUNOPATHOLOGY OF HEPATITIS B AND C VIRUS INFECTIONS

Overview of Research Problems Investigated:

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major human pathogens affecting millions of people worldwide. They cause a broad spectrum of liver diseases, ranging from asymptomatic (occult infection), through acute and chronic hepatitis, to cirrhosis and hepatocellular carcinoma (HCC). Approximately every tenth person in the word is chronically infected with one of these viruses. However, up to 35% of the global population has been exposed to HBV or HCV and may carry virus at the levels detectable only by highly sensitive virus genome detection techniques. There is an effective vaccine to prevent HBV infection, but not against HCV. Currently, there is no treatment to completely eradicate progressing HBV or HCV infection. Both viruses do not kill liver cells directly, but they cause disease by inducing virus-specific and nonspecific host immune responses. For this reason, viral hepatitis B and C are considered to be immunological diseases. It became evident that both HBV and HCV not only infect the liver but also the host’s immune (lymphatic) system.

Molecular Virology and Hepatology Research Group

Dr. Michalak's laboratory has established a multidisciplinary expertise in viral hepatitis and antiviral research that is conducive to graduate and postgraduate training. The research has been supported by operating grants and student scholarships from the Canadian Institutes of Health Research, Canadian Liver Foundation, National CIHR Research Training Program in Hepatitis C (NCRTP-HepC), Canadian Blood Services and Memorial University, and by research contracts and grants from international and Canadian pharmaceutical and biotechnology companies. Dr. Michalak is the Senior (Tier 1) Canada Research Chair in Viral Hepatitis/Immunology.

Current Research Focus:

  • the molecular and immunological mechanisms of HBV and HCV persistence.
  • the role of HBV and HCV lymphotropism and the host’s immune system in the maintenance and control of occult (i.e., clinically unapparent but molecularly evident) long-term virus infection.
  • the role of the virus-specific and innate immune responses and autoimmunity in the pathogenesis of liver injury in viral hepatitis.
  • the development of cell culture models for HCV and HBV propagation in vitro applicable for basic virus research and testing antiviral compounds.
  • the development of new reagents and assays for studies on molecular and immunological events in the woodchuck animal model of hepatitis B.
  • the development and evaluation of novel antiviral agents and therapies against HBV and HCV infections.

Special Facilities and Expertise:

1. A colony of Eastern North American woodchucks (Marmota monax) susceptible to woodchuck hepatitis virus (WHV), a natural model of human HBV infection and hepatitis B. This model accurately reflects the virological, immunological, and pathological events occurring in HBV infection and is applicable for basic investigations and for evaluations of antiviral agents and preventative strategies against hepatitis B. The model is available for selected collaborative and contractual research.

2. A cell culture-system for replication of wild-type HCV. This model employs normal human lymphoid cells permissive to HCV infection. It can be used to study the efficacy of antiviral agents in culture.

Recent Refereed Publications:

Sarhan, M.A., Pham, T.N.Q., Chen, A.Y. & Michalak, T.I. (2012). Hepatitis C virus infection of human T lymphocytes is mediated by CD5. Journal of Virology (in press).

Pham, T.N.Q., Coffin, C.S., Churchill, N.D., Urbanski, S.J., Lee, S.S. & Michalak, T.I. (2012). Hepatitis C virus persistence after sustained virological response to antiviral therapy in patients with or without past exposure to hepatitis B virus. Journal of Viral Hepatitis 19: 103-111.

Guy, C.S., Rankin, S.L. & Michalak, T.I. (2011). Hepatocyte cytotoxicity is facilitated by asialoglycoprotein receptor. Hepatology 54: 1043-1050.

Coffin, C.S., Mulrooney-Cousins, P.M., van Marle, G., Roberts, J.P., Michalak, T.I. & Terrault N.A. (2011). Hepatitis B virus quasispecies in hepatic and extrahepatic viral reservoirs in liver transplant recipients on prophylactic therapy. Liver Transplantation 17: 955-962.

Coffin, C.S., Mulrooney-Cousins, P.M., Peters, M.G., van Marle, G., Roberts, J.P., Michalak, T.I. & Terrault N.A. (2011). Molecular characterization of intrahepatic and extrahepatic hepatitis B virus (HBV) reservoirs in patients on suppressive antiviral therapy. Journal of Viral Hepatitis 18: 415-423.

Lin, L.T., Noyce, R.S., Pham, T,N.Q., Wilson, J.A., Sisson, G.R., Michalak, T.I., Mossman, L.L. & Richardson, C.D. (2010). Replication of subgenomic HCV replicons in mouse fibroblasts is facilitated by deletion of interferon regulatory factor-3 and expression of liver-specific microRNA-122. Journal of Virology 84: 9170-9180.

Pham, T.N.Q., Coffin, C.S. & Michalak, T.I. (2010). Occult hepatitis C virus infection: what does it mean? Liver International 30: 502-511.

Gujar, S.A. Jenkins, A.K., MacParland, S.A. & Michalak, T.I. (2010). Pre-acute hepadnaviral infection is associated with activation-induced apoptotic death of lymphocytes in the woodchuck (Marmota monax) model of hepatitis B. Developmental and Comparative Immunology 34: 999-1008.

Guy, C.S., Wang, J. & Michalak, T.I. (2010). Hepadnaviral infection augments hepatocyte cytotoxicity mediated by both CD95 ligand and perforin pathways. Liver International 30: 396-405.

Pham, T.N.Q., Mercer, S.E. & Michalak, T.I. (2009). Chronic hepatitis C and persistent occult hepatitis C virus infection are characterized by distinct immune cell cytokine expression profiles. Journal of Viral Hepatitis 16: 547-556.

MacParland, S.A., Pham, T.N.Q., Guy, C.S. & Michalak, T.I. (2009). Hepatitis C virus persisting after clinically apparent sustained virological response to antiviral therapy retains infectivity in vitro. Hepatology, 49: 1431-1441.
Accompanied by the News Research Alert issued by the American Association for the Study of Liver Diseases and Willey-Blackwell entitled; “Patients with Resolved Hepatitis C Likely Still Contagious”, which was disseminated to the news agencies worldwide. Among others, the data were summarized by Dr. Will Boggs in a news briefing entitled; “Hepatitis C Still Contagious after Infection Clears” published by Reuters Health of the Reuters News Agency, New York.

Michalak, T.I., Zhang, H., Churchill, N.D., Larsson, T., Johansson, N.-G. & Öberg, B. (2009). Profound antiviral effect of oral administration of MIV-210 on chronic hepadnaviral infection in a woodchuck model of hepatitis B. Antimicrobial Agents and Chemotherapy 53: 3803-3814.

Pachiadakis I., Chokshi, S., Cooksley, H., Farmakiotis D., Sarrazin, C., Zeuzem, S., Michalak, T.I. & Naoumov, N.V. (2009). Early viremia clearance during antiviral therapy of chronic hepatitis C improves dendritic cell functions. Clinical Immunology 131: 415-425.

Raimondo, G., Allain, J.-P., Brunetto, M.R., Buendia, M.-A., Chen, D.-S., Colombo, M., Craxi, A., Donato, F., Ferrari, C., Gaeta, G.B., Gerlich, W.H., Levrero, M., Locarnini, S., Michalak, T.I., Mondelli, M.U., Pawlotsky, J.-M., Pollicino, T., Prati, D., Puoti, M., Samuel, D., Shouval, D., Smedile, A., Squadrito, G., Trepo, C., Villa, E., Will, H., Zanetti, A.R., Zoulim, F. (2008). Statements from the Taormina expert meeting on occult hepatitis B virus infection. Journal of Hepatology 49: 652-657.

Guy, C.S., Mulrooney-Cousins, P.M., Churchill, N.D. & Michalak, T.I. (2008). Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus. Journal of Virology 82: 8579-8591.

Mulrooney-Cousins, P.M. & Michalak, T.I. (2008). Repeated passage of wild-type woodchuck hepatitis virus in lymphoid cells does not generate cell type-specific variants or alter virus infectivity. Journal of Virology 82: 7540-7550.

Gujar, S.A., Guy, C.S., Wang, J. & Michalak, T.I. (2008). Aberrant lymphocyte activation precedes delayed virus-specific T-cell response after both primary infection and secondary exposure to hepadnavirus in the woodchuck model of hepatitis B virus infection. Journal of Virology 82: 6992-7008.

Pham, T.N.Q., King, D., MacParland, S.A., McGrath, J.S., Reddy, S.B., Bursey, F.R. & Michalak, T. I. (2008). Hepatitis C virus replicates in the same immune cell subsets in chronic hepatitis C and occult infection. Gastroenterology 134: 812-822

Guy, C.S., Rankin, S., Wang, J. & Michalak, T.I. (2008). Hepatocytes express perforin and can mediate apoptosis of susceptible target cells via granule exocytosis. Hepatology 47: 1692-1701.

Pham, T.N.U., Mulrooney-Cousins, P.M., Mercer, S.E., MacParland, S.A., Inglot, M., Zalewska, M., Simon, K. & Michalak, T.I. 2007. Antagonistic expression of hepatitis C virus and alpha interferon in lymphoid cells during persistent occult infection. Journal of Viral Hepatitis 14: 537-548

Wang, J., Gujar, S.A., Cova, L. & Michalak, T.I. 2007. Bicistronic woodchuck hepatitis virus core and gamma interferon DNA vaccine can protect from hepatitis but does not elicit sterilizing antiviral immunity. Journal of Virology 81: 903-916.

MacParland, S.A., Pham, T.N.Q., Gujar, A.S. & Michalak, T.I. 2006. De novo infection and propagation of wild-type hepatitis C virus in human T lymphocytes in vitro. Journal of General Virology 87: 3577-3586

Wang, J. & Michalak, T.I. 2006. Inhibition of woodchuck hepatitis virus class 1 major histocomaptibility complex presentation on hepatocytes is mediated by virus envelope pre-S2 protein and can be restored by treatment with gamma interferon. Journal of Virology 80: 8541-8553.

Guy, C.S., Wang, J. & Michalak, T.I. 2006. Hepatocytes as cytotoxic effector cells can induce cell death by CD95 ligand-mediated pathway. Hepatology 43: 1231-1240.
Accompanied by the Editor commentary written by Dr. Neil Kaplowitz published in Hepatology Highlights entitled: “Killer Hepatocytes Fight Back”, Hepatology 2006; 44 : 285.

Pham T.N.Q., MacParland S.A., Coffin C.S., Lee S.S., Bursey F.R., and Michalak T.I. 2005. Mitogen-induced upregulation of hepatitis C virus expression in human lymphoid cells. Journal of General Virology 86: 657-666.

Gujar S.A. and Michalak T.I. 2005. Flow cytometic quantitation of T cell proliferation and division kinetics in woodchuck model of hepatitis B. Immunol. Invest. 34: 215-236.

Wang J. and Michalak T.I. 2005. Comparison of biological activity of recombinant woodchuck interferon gamma and tumor necrosis factor alpha produced in baculovirus and Escherichia coli expression systems. Cytokine 30: 22-34.

Coffin C.S., Pham T.N.Q., Mulrooney P.M., Churchill N.D., and Michalak T.I. 2004. Persistence of isolated antibodies to woodchuck hepatitis virus core antigen is indicative of occult infection. Hepatology 40: 1053-1061.

Pham T.N.Q., MacParland S.A., Mulrooney P.M., Cooksley H., Naoumov N.V., and Michalak T.I. 2004. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. Journal of Virology 78: 5867-5874.
Accompanied by: A commentary in the Clinical Care Option for Hepatitis, July 2004, written by Anna Poppa:" Ultrasensitive testing detects persistent HCV RNA in patients with resolved HCV infection"; Review in Hepatitis Journal Options, July 2004, by Dr. Geoffrey M. Dusheiko: "Minute amounts of residual HCV RNA should not deter antiviral therapy"; Editorial in Hepatology, 2005 Jan., written by Drs. Jordan J. Feld and T. Jake Liang: "HCV persistence: Cure is still a four letter word"; Review in Liver Transplantation, 2005 Jan. written by Drs. M. Radkowiski and T. Laskus: "Persistence of hepatitis C virus after successful treatment of chronic hepatitis C: Is hepatitis C infection for life?"; Summary and Comment in JournalWatch Gastroenterology, 2005 Feb., by Dr. Kenneth D. Flora: "Does HCV ever really go away?".

Michalak T.I., Mulrooney P.M., and Coffin C.S. 2004. Low doses of hepadnavirus induce infection of the lymphatic system that does not engage the liver. Journal of Virology 78: 1730-1738.

Diao J., Slaney D.M., and Michalak T.I. 2003. Modulation of the outcome and severity of hepdnaviral hepatitis in woodchucks by antibodies to hepatic asialoglycoprotein receptor. Hepatology 38: 629-638.

Mulrooney P.M. and Michalak T.I. 2003. Quantitative detection of hepadnavirus-infected lymphoid cells by in situ PCR combined with flow cytometry: implications for the study of occult virus persistence. Journal of Virology 77: 970-979.

Hodgson P.D. and Michalak T.I. 2001. Augmented hepatic interferon gamma expression and T cell influx characterize acute hepatitis progressing to recovery and residual lifelong virus persistence in experimental adult woodchuck hepatitis virus infection. Hepatology 34: 1049-1059.
Accompanied by the Editor’s note in the Hepatology Highlights: "T-cells, Th1 cytokines, Woodchucks and HBV Outcome: It all Fits." Hepatology 2002; 35: 2.

Lew Y.-Y. and Michalak T.I. 2001. In vitro and in vivo infectivity and pathogenicity of the lymphoid cell-derived woodchuck hepatitis virus. Journal of Virology 75: 1770-1782.

Michalak T.I., Hodgson P.D., and Churchill N.D. 2000. Posttranscriptional inhibition of class I major histocompatibility complex presentation on hepatocytes and lymphoid cells in chronic woodchuck hepatitis virus infection. Journal of Virology 74: 4483-4494.

Coffin C.S. and Michalak T.I. 1999. Persistence of infectious hepadnavirus in the offspring of woodchuck mothers recovered from viral hepatitis. Journal of Clinical Investigation 104: 203-212.
Accompanied by the Editor’s note: "A Mother and Child Union in Hepatitis Virus", Journal of Clinical Investigation 104: vii.

Michalak T.I., Pardoe I.U., Coffin C.S., Churchill N.D., Freake D.S., Smith P., and Trelegan C.L. 1999. Occult life-long persistence of infectious hepadnavirus and residual liver inflammmation in woodchucks convalescent from acute hepatitis. Hepatology 29: 928-938.


Recent Invited Publications and Proceedings:

Pham, T,N,Q. & Michalak, T.I. (2011). HCV infection of hematopoietic and immune cell subsets. In: “HCV and Cryoglobulinemia”. Ed.: Franco Dammacco. Springer Verlang Publishing Company, Basel, Switzerland; pp. 69-75.

Pham, T,N,Q. & Michalak, T.I. (2011). Occult hepatitis C virus infection and its relavanve in clinical practice. Journal of Clinical and Experimental Hepatology 1: 185-189 (invited contribution to “From Bench To Bedside”

Guy, S.C. & Michalak, T.I. (2011). Hepatocyte cytotoxic avtivity and its physiological and pathological relevance. In: “Hepatocytes: Biology, Functions and Roles in Disease”. Nova Science Publishers, Inc., Hauppaige, NY ( in press).

Mulrooney-Cousins, P.M. & Michalak, T.I. (2011). New aspects of natural history and pathogenicity of hepadnaviral infection and hepatocyte function revealed by the woodchuck model of hepatitis B. In: “Liver Biopsy in Medicine”. InTech Publishing Company, Vienna; pp. 355-378.

Michalak, T.I. (2010). Immune cell reservoirs of persisting hepatitis C virus. Gut 59: 867-868 (commentary commissioned by the Editor of the Gut).

Michalak, T.I. & Pham, T.N.Q. (2009). Anti-HCV core antibody: a potential new marker of occult and otherwise serologically silent HCV infection. Journal of Hepatology 50: 244-246 (invited editorial).

Mulrooney-Cousins, P.M. & Michalak, T.I. (2009). Diagnostic assays for hepatitis B. In: “Hot Topics in Viral Hepatitis: Management of Hepatitis B in 2009”. Ed.: Francesco Negro. FB Communication, Modena, Italy; 15: 7-13 (invited chapter).

Guy, C.S. & Michalak, T.I. (2008). Hepatocytes as cytotoxic effector cells. Current Immunology Reviews 4: 215-220.

Pham, T.N.Q. & Michalak, T.I. (2008). Occult persistence and lymphotropism of hepatitis C virus infection. World J. Gastroenterol. 14: 2789-2793 (editorial)

Mulrooney-Cousins, P.M. & Michalak, T.I. (2007). Persistent occult hepatitis B virus infection: experimental findings and clinical implications. World J. Gastroenterol. 13: 5682-5686 (editorial)

Michalak, T.I., Pham T.N.Q. & Mulrooney-Cousins, P.M. 2007. Molecular diagnosis of occult HCV and hepadnaviral persistence. Future Virology 2: 451-465.

Michalak, T.I., 2007. Characteristics and consequences of experimental occult hepatitis B virus infection in the woodchuck model of hepatitis B. Current Topics in Virology 6: 1-13

Pham, T.N.Q. & Michalak, T.I. 2006. Occult hepatitis C virus persistence: identification and characteristics. Med. Lab. Observ. 38: 20-22.

Michalak T.I. 2004. Immunology of hepatitis B. In: Hepatitis Prevention and Treatment. Eds.: Colacino, J. and Heinz, B.A. Birkhäuser Verlag, Switzerland. pp. 87-105.

Hodgson P.D. and Michalak T.I. 2004. Occult hepadnavirus persistence is accompanied by hepatic IFN( and TNF" upregulation and residual liver infammation. Proceedings of the 11th International Symposium of Viral Hepatitis and Liver Diseases. Eds.: Jilbert. A.R., Grgacic, E.V.L., Vickery, K., Burrell, C.J., Cossart, Y.E. The Australian Centre for Hepatitis Virology, Melbourne, Australia. pp. 332-334.

Churchill N.D. and Michalak T.I. 2004. Woodchuck hepatitis virus hepatocyte culture models. In: Hepatitis B and D Protocols, vol. 2. Eds.: Hamatake R.K. and Lau, J.Y.N. pp. 175-187.

Michalak T.I. 2000. Occult persistence and lymphotropism of hepadnaviral infection: Insights from the woodchuck viral hepatitis model. Immunology Reviews. 174: 98-111.

List of publications available from PubMed.


Current Postdoctoral Fellows and Graduate Students and their Research Interests:

Mohamed Sarhan - Ph.D. student.
Project title: “Hepetitic C Virus Infection of Immune Cells”. (supported by The National Canadian Research Training Program in Hepatitis C).

Georgia Skardasi - M.Sc. student.
Project Title: "Hepatitis C Virus Detection of Human Primary T Cells". (supported by The National Canadian Research Training Program in Hepatitis C).
J. Bradley Williams - M.Sc. student.
Project Title: "Woodchuck TLRs-Identification and Expression in the Curse of Experimental Hepadnaviral Infection". (supported by CIHR Banting and Best Canada Graduate Scholarship - Masters Award).


Some Former Graduate Students and Associates and their Current Positions:

Dr. Tram N.Q. Pham, Ph.D. - Postdoctoral Fellow, Institute de Recherches Cliniques du Montreal.
Project title: "Molecular Pathogenesis of Hepatitis C Virus Persistence".

Dr. Sonya A. MacParland, Ph.D. - Postdoctoral Fellow, University of Toronto, Toronto, ON.
Thesis title: "Persistence and Lymphotropism of Hepatitis C Virus".

Dr. Shashi A. Gujar - D.M.V., Ph.D. - Postdoctoral Fellow, Dalhousie University, Halifax.
Thesis Title: "Role of Lymphatic System in Persistence and Pathogenesis of Woodchuck Hepatitis Virus Infection".

Dr. Clifford S. Guy - B.Sc. (Hons), Ph.D.; Postdoctoral Fellow, St. Jude Children's Research Hospital, Memphis, TN
Thesis Title: "Intrahepatic Innate Immunity in Hepadnaviral Infection in the Woodchuck Model of Hepatitis B".

Dr. Jinguo Wang – M.D., Ph.D Postdoctoral Fellow, University of Calgary, Calgary.
Thesis title: "Effect of Antiviral Cytokines on Hepadnavirus Replication and Liver Disease in Experimental Hepatitis B".

Dr. Patricia M. Mulrooney-Cousins, Ph.D. - Manager of Woodchuck Hepatitis Research Facility, Faculty of Medicine, Memorial University, St. John's, NL.
Thesis title: "Hepadnaviral Lymphotropism and Its Role in Virus Persistance in the Woodchuck Model of Hepatitis B".

Dr. Dr. Paul Hodgson, M.Sc., Ph.D., M.B.A. - Associate Director, VIDO-InterVac, University of Saskatchewan, Saskatoon, Saskatchewan.
Thesis Title: "Mechanisms of the Pathogenesis of Cell Injury and Viral Persistence in the Woodchuck Model of Hepatitis B".

Dr. Darlene Slaney, B.Sc. (Hons), M.D.; Anesthesiologist, University of Saskatchewan, Saskatoon, Saskatchewan.
Thesis Title: "Evaluation of the Expression of Selected Cellular Genes as Potential Markers of Hepatocellular Carcinoma"

Yuan Lew, M.Sc., M.B.A. Business Development Officer, Technology Development and Commercialization, University Health Network, Toronto, Ontario.
Thesis Title: "Infectivity of Lymphoid Cell-Derived Woodchuck Hepatitis Virus in an In Vitro Experimental system."
Dr. Carla Coffin, B.Sc. (Hons), M.Sc., M.D., FRCPC; Assistant Professor, University of Calgary, Calgary, Alberta.
Thesis Title: "Hepadnavirus Persistence in Offspring Born to Mothers Convalescent from Viral Hepatitis in the Woodchuck Model".

Dr. Jingyu Diao, M.Sc., Ph.D. - Scientist, Genetech, San Francisco, CA.
Thesis Title: "Pathogenesis of Liver Injury: Virus-Induced Autoantibody Response against Asialoglycoprotein Receptor in Woodchuck (Marmota monax) Viral Hepatitis".

Dr. Charles Yi-Ming Jin, M.D., M.Sc.; Assistant Professor of Psychiatry, New York University School of Medicine and Albert Einstein College of Medicine, Medical and Fellowship Training Director, Division of Addiction Psychiatry; Attending Physician, Division of Child Psychiatry, North Shore University Hospital, New York.
Thesis Title: "Identification and Characterization of a Novel Class of a Receptor for Encephalomyocarditis Virus in Human Cells".