Department of Medical Microbiology & Immunology
University of Alberta
Department of Medicine & Dentistry
6-142F Katz Group Centre
Edmonton, Alberta T6G 2E1
Phone: (780) 492-3119
Fax: (780) 492-7521
- Assistant Professor, Department of Medical Microbiology & Immunology, University of Alberta
- Canada Research Chair in Viral Pathogenesis Tier II
Respiratory Virus Infection - Our laboratory investigates the virology and host-cell response to respiratory virus infections. Viruses that infect the airways and lungs, like seasonal influenza and Respiratory Syncytial Virus (RSV) are the greatest causes of pediatric hospital admissions in North America. Pandemic influenza causes significant morbidity and mortality in the young and elderly alike, and the 2009 H1N1 influenza pandemic taught us many lessons about the enhanced susceptibility of individuals with preexisting health conditions to respiratory virus infections. However, there is still much that needs to be learned about influenza, RSV and the host cell response to respiratory viral infection (to understand how the viruses make us sick). We investigate the cellular receptor proteins that viruses need to use to enter the host cell (viruses use their cellular receptor much like a lock and key to enter a host cell), and the cellular signalling queues activated by incoming virus particles that initiate the virus entry program into the host cell. Furthermore, while investigating interactions of drugs with viruses we have discovered that some drugs can enhance viral infection by creating a cell-signalling environment that is favourable to virus replication. By investigating viral replication and the host response to virus infection we can understand viral pathology, develop the basis for new treatments and refine existing treatment methods.
Respiratory Syncytial Virus Receptors - Our discovery of the Respiratory Syncytial Virus (RSV) receptor, nucleolin, has led to us investigating the interactions between nucleolin and RSV. Virus receptors are logical therapeutic targets since virus-receptor binding is the first step of the virus replication cycle; blocking virus replication before it starts. Nucleolin is a protein that exists throughout the cell, in the nucleus, cytoplasm and on the plasma membrane of airway epithelial cells. At the plasma membrane, nucleolin interacts with the RSV fusion protein (RSV-F) to trigger entry of RSV into bronchial epithelial cells that line the airway. Binding by RSV to cellular receptors leads to activation of cellular signalling queues, triggered by the entering virus to stimulate internalization of virus particles into the cell. Our research team is investigating the signalling triggered by receptor binding and how these events lead to successful virus infection. More importantly, we are developing ways to block virus signalling that is required for virus replication as the basis for new antiviral drugs. Virus receptor binding and virus entry signalling queues are desirable facets of investigation because synthetic molecules can block them, leading to new antiviral drugs.
Investigating Respiratory Viruses - To investigate respiratory virus infections our laboratory uses several different methods of assay. New virus-host interactions are discovered using proteomic (mass spectrometry) and genomic approaches (ChIP-SEQ, siRNA screens) to identify novel pathways and processes. Confocal immunofluorescence imaging is used to observe these new virus-host interactions, like virus entry and the dynamics of virus-cell receptor interactions. Imaging, biochemical assays and infectivity studies are all mutually supportive of new biological models of virus infection. Finally, we use imaging for direct observation of, not only virus interactions with the cell but the action of new antivirals on virus replication to verify antiviral mechanisms.
Figure 3. Model of Respiratory Syncytial Virus (RSV) binding its nucleolin receptor and virus entry.
1. Farnoosh Tayyari*, David Marchant*, Theo Moraes, Wenming Duan, Peter Mastrangelo, Richard G Hegele†. Identification of Nucleolin as a cellular receptor for Respiratory Syncytial Virus. Nature Medicine. Aug 14;17(9):1132-5. 2011.
2. David Marchant, Gurpreet Singerha, Jonathan Boyd, Soraya Utokaparch, Zongshu Luo, Xioaning Si, Delbert R. Dorscheid, Bruce M McManus and Richard G Hegele. Toll-Like Receptor 4 Mediated p38 Mitogen Activated Protein Kinase Activation is a Determinant of Virus Tropism. Journal of Virology. Nov;84(21):11359-73. 2010.
3. Farshid S. Garmaroudi, David Marchant, Xiaoning Si, Abbas Khalili, Brian W. Wong, Aline Tabet, Raymond Ng, Kevin Murphy, Honglin Luo and Bruce M. McManus. Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection, Proceedings of the National Academy of Sciences (USA), 2010 Sep 28;107(39):17053-8. Epub 2010 Sep 10
4. David Marchant, Xiaoning Si, Alhousseynou Sall, Thomas Abraham, Winnie Wu, Zongshu Luo, Tamar Petersen, Richard G Hegele and Bruce M McManus. ERK MAP kinase activated Arf6 trafficking is detrimental to CVB3 infection of HeLa cells. Journal of General Virology, Apr;90(Pt 4):854-862. (2009).
5. David Marchant*, Ying Dou*, Honglin Luo*, John E McDonough, Xiaoning Si, Elizabeth Walker, Zongshu Luo, Arash Tehrani, Anders Arner, Richard G Hegele, Ismail Laher, and Bruce M McManus. Bosentan Improves Cardiac Function while Enhancing Viral Load via p38 MAP Kinase Activation during Coxsackievirus-Induced Myocarditis. Circulation Research, Mar 27;104(6):813-21 (2009).
Farnoosh Tayyari*, David Marchant* and Richard G Hegele*. A novel cell surface receptor for Human Respiratory Syncytial Virus. 09-123. USPTO number, US 61/202,791.
Members of our team:
- Leanne Bilawchuk (Laboratory Manager)
- Cameron Griffiths (Graduate Student)
- Lionel Jensen (Graduate Student)