Robert Geraghty, Ph.D.

Associate Professor, Center for Drug Design
Associate Director, Center for Drug Design

Contact information
 
Office: 7-222 Phillips Wangensteen Building
Phone: 612-625-3281
E-mail: gerag012@umn.edu

Education
B.S., University of Minnesota, Twin Cities, 1988
Ph.D., University of Wisconsin, 1995

Research Interest

Herpesviruses

Herpesviruses are significant causes of morbidity and mortality worldwide.  My lab is interested in understanding how herpesviruses enter host cells.  We study the alpha herpesviruses, such as herpes simplex virus type 1 (HSV-1), as model herpesviruses.  Herpesvirus virions are enveloped by a lipid bilayer obtained from the host cell and that bilayer is studded with viral envelope glycoproteins.  The glycoproteins help the virus evade host immune responses as well as to mediate the attachment and fusion of the viral particle with the host cell.  This is a critical step in virus replication because the virus must gain entry into the cell to replicate.  Whereas most viruses use one or two surface proteins to enter host cells, HSV-1 uses at least 5 surface glycoproteins to enter host cells.  There are four envelope glycoproteins (gB, gD, gH and gL) that are necessary and sufficient for membrane fusion induced by HSV-1 and these form the core membrane fusion machinery.  One of the glycoproteins, gD, must bind a cell-surface receptor for membrane fusion and virus entry to occur.  We have previously identified cell-surface receptors for HSV-1 entry and analyzed the structure/function relationship of one cell-surface receptor, nectin-1.  We also study the molecular mechanism of the fusion event.  We have identified a hemifusion intermediate in the HSV-1 fusion process.  We are conducting extensive mutagenesis on the glycoproteins of the core fusion machinery and testing those mutants in virus entry and cell fusion assays to shed light on the role each glycoprotein plays in the fusion process.  We are also examining the protein-protein interactions required for membrane fusion using fluorescence resonance energy transfer and other advanced microscopy techniques.  A thorough understanding of the molecular details of virus entry will facilitate the design of anti-viral therapies to block the process.

RNA viruses

Many viruses with RNA genomes have emerged in the last thirty years to cause debilitating and deadly disease throughout the world.  These viruses include human immunodeficiency virus, hepatitis viruses, west nile virus, dengue virus, respiratory syncytial virus and others.  We are interested in identifying known and novel small molecules with anti-viral activity against these viruses.  We are also pursuing the discovery and characterization of novel targets for anti-viral intervention.

Selected Publications

Geraghty, R.J., Krummenacher, C., Cohen, G.H., Eisenberg, R.J., Spear, P.G., (1998)  Entry Of Alphaherpesviruses Mediated By Poliovirus Receptor-Related Protein 1 And Poliovirus Receptor.  Science 280:1618-1620.

Geraghty, R.J., Jogger, C.R., Spear, P.G., (2000)  Cellular Expression Of Alphaherpesvirus gD Interferes With Entry Of Homologous And Heterologous Alphaherpesviruses By Blocking Access To A Shared gD Receptor.  Virology 268:147-158.

Geraghty, R.J., Krummenacher, C., Cohen, G.H., Eisenberg, R.J., Spear, P.G., (2001)  Use Of Chimeric Nectin-1(HveC)-Related Receptors To Demonstrate That Ability To Bind gD Is Not Necessarily Sufficient For Alphaherpesvirus Entry.  Virology 285:366-375.

Jones, N.A. and R.J. Geraghty, (2004)  Fusion Activity Of Lipid-Anchored Envelope Glycoproteins Of Herpes Simplex Virus Type 1.  Virology 324(1):213-228.

Subramanian, R.P., J.E. Dunn, and R.J. Geraghty, (2005)  The Nectin-1a Transmembrane Domain, But Not The Cytoplasmic Tail, Influences Cell Fusion Induced by HSV-1 Glycoproteins.  Virology 339:176-191. [Cover photograph]

Klyachkin, Y.M., K.D. Stoops and R.J. Geraghty, (2006)  Herpes Simplex Virus Type 1 Glycoprotein L Mutants That Fail To Promote Trafficking of Glycoprotein H And Fail To Function In Fusion Can Induce Binding Of Glycoprotein L-Dependent Anti-Glycoprotein H Antibodies.  Journal of General Virology  87:759-767.

Even, D.L., Henley, A.M., and R.J. Geraghty, (2006)  The Requirements For Herpes Simplex Virus Type 1 Cell-Cell Spread Via Nectin-1 Parallel Those For Virus Entry.  Virus Research 119:195-207.

Subramanian, R.P. and R.J. Geraghty, (2007)  Herpes Simplex Virus Type-1 Mediates Fusion Through a Hemifusion Intermediate by Sequential Activity of Glycoproteins D, H, L, and B.  Proceedings of the National Academy of Sciences 104(8):2903-2908.  SA, (2) 

Klyachkin, Y.M. and R.J. Geraghty, (2008)  Mutational Analysis of Herpes Simplex Virus Type 1 Glycoprotein L Reveals The Importance Of An Arginine-Rich Region For Function.  Virology 374(1): 23-32.

A detailed publication and patent list is also available.