Bruce M. McManus
UBC - St Paul's Hosp
iCAPTURE Ctr, Dept Pathol and Lab Med
1081 Burrard St
Vancouver, BC V6Z 1Y6
Canada
BMcManus@mrl.ubc.ca
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Enteroviral infections.

Abstract:
UBC McDonald Research Laboratories/The iCAPTUR⁴E Center,
Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care-University of British Columbia, Vancouver, Canada

Enteroviruses such as coxsackieviruses and echoviruses, as well as adenoviruses and influenza viruses, are common and worldwide agents that cause inflammatory heart muscle injury or myocarditis and subsequent dilated cardiomyopathy.  Coxsackievirus B3 (CVB3), an enterovirus of the family Picornaviridae, is a major causative agent for human viral myocarditis.  Work by our group and others has led to revision of the paradigm of predominantly immune-mediated damage in this condition by revealing extensive direct virus infection as a major contributor to myocardial damage (McManus et al, 1993, Clin Immunol Immunopathol., 68: 159).  In this regard, through the use of a combination of infectomical and bioinformatical approaches, further supported by well-established molecular, histological and functional tools, we are increasing our understanding of CVB3 pathogenesis.  Our genomic strategies include mRNA differential display, cDNA arrays and oligonucleotide GeneChips^â (Affymetrix, Inc., CA), applied both in cell culture and in the mouse model to characterize host gene responses (Taylor et al, Circ Res, 2000, 87: 328; Yang et al, Circ Res, 1999, 84: 704), and for investigation of viral genomics (Yang et al, Virology, 1999, 265: 206).  Using these tools, we are continuing to dissect out important host transcriptional events relevant to viral infection, and in doing so, accelerate our hypothesis-driven research.  We are currently investigating global transcriptional changes in cellular systems as relate to metabolism, immediate early and apoptosis signaling, cell defense, architecture, and cell cycle.  We have shown that CVB3 triggers the pro-survival mitogen-activated protein kinase-ERK pathway, followed by transcription of downstream genes, and that such events are necessary for virus replication (Luo et al, J Virol, 2002, 76: 3365).  We have also found that the pro-apoptotic Bcl-2 family protein, Nip21, plays an important role in regulating virus replication and host cell viability through the caspase-mediated death cascade (Zhang et al, Circ Res, 2002, 90: 1251).  Viral infection also disrupts, and even halts, important cellular systems involved in host protein degradation and cell cycle regulation (Luo et al, J Virol, 2003, 77: in press).  Thus, through a multifaceted approach aimed at a better understanding of the complex interaction between virus replication and pathogenesis, including the host cell response, our overarching goal is to gain insights into how the target cell - virus duel influences disease progression in the heart from times of greatest direct viral injury, to inflammation, and finally to repair.  By dissecting out the virus- versus host-beneficial events, we may uncover novel biological points for intervention and improvement of disease outcome.
 

Supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of British Columbia and Yukon, the Heart and Stroke Foundation of Canada, and the Michael Smith Foundation for Health Research.