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Biographical
Sketch
Dr. Smith received his B.A. degree in microbiology
from the University of California, Santa Barbara. He earned his Ph.D. degree in microbiology from the University of Pennsylvania where he studied the actin-based motility of the bacterial pathogen, Listeria monocytogenes, in the
laboratory of Dr. Daniel Portnoy. He received post-doctoral training in the laboratory of Dr. Lynn Enquist at Princeton University, where he began studies of alpha-herpesvirus spread in the nervous system. Dr. Smith joined Northwestern University Medical School
as an assistant professor in 2001.
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Research
Description
Our research focus is on the molecular and cellular
biology of alpha-herpesvirus spread in the vertebrate nervous system. Novel methods adapted from bacterial genetics are used to efficiently make mutant viruses, and these viruses are then studied during the course of cellular infection. Fluorescence and video microscopy are used to
examine viral transport in living cultured neurons, and pathogenesis can be studied using animal models. Viral factors involved in virus spread are further studied by in vitro methods to identify interactions with cellular proteins.
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Research
Abstract
My research interests center on understanding the mechanisms by which infectious agents cause disease, specifically with regard to
the cell biology of host/pathogen interactions. I am currently investigating the relationship between infection of the nervous system by herpesviruses, and disease outcome. Some of the most traumatic diseases result from infections of the nervous system. Diseases such as polio, rabies and
encephalitis are typically debilitating or lethal. In contrast, herpesviruses are highly proficient at infecting the nervous system, yet normally do not cause neurological disease. This is achieved in part by self-imposed restrictions encoded within the viruses that limit viral
reproduction and prevent dissemination into the brain. For the individual, this results in a relatively benign infection, yet the virus becomes a life-long occupant of the nervous system that will periodically reemerge at body surfaces to infect others. Unfortunately, this infectious cycle
can go awry resulting in several forms of severe disease (such as keratitis or encephalitis).
By developing methods to genetically manipulate herpesviruses efficiently, and visualize individual viruses in living neurons,
we are studying the mechanisms by which the virus achieves its stringently controlled life cycle. Current genetic manipulations are based on a full-length infectious clone of the herpesvirus genome. The clone was made as a bacterial artificial chromosome (BAC) in E. coli. Transfection of purified
E. coli BAC plasmid into permissive eukaryotic cells is sufficient to initiate viral infection, allowing for immediate examination of viral mutant phenotypes in a variety of biological assays. For
example, by fusing the green fluorescent protein (GFP) to a structural component of the viral capsid, individual viral particles can be tracked within the axons of living neurons during both entry and egress phases of the infectious cycle. Studies in culture can be complemented by
examining the pathogenesis of mutant viruses in rodent models of infection.
Using these methods, we have discovered key aspects of
cellular infection, viral assembly and intracellular transport. Looking forward, we are continuing to pursue our multidisplinary approach of combining neuroscience, cell biology, bacterial genetics and virology to better understand these important pathogens.
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Publications (Click on icons at left to link to
the abstract)
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Portnoy, D.A., G.A. Smith.
1992. Devious devices of Salmonella. Nature. 357:536-537
(News and Views)
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Brundage, R.A., G.A. Smith,
A. Camilli, J.A. Theriot, D.A. Portnoy. 1993. Expression and
phosphorylation of the Listeria monocytogenes ActA protein
in mammalian cells. Proc. Natl. Acad. Sci. USA. 90:
11890-11894
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Smith, G.A., H. Marquis, S. Jones, N.C. Johnston, D.A. Portnoy, H.
Goldfine. 1995. The two distinct phospholipases C of Listeria
monocytogenes have overlapping roles in escape from a vacuole
and cell-to-cell spread. Infect. and Immun. 63(11): 4231-4237 |
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Smith, G.A., D.A.
Portnoy, J.A. Theriot. 1995. Asymmetric distribution of the
Listeria monocytogenes ActA protein is required and sufficient
to direct actin-based motility. Mol. Micro. 17(5): 945-951
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Smith, G.A., J.A. Theriot, D.A. Portnoy. 1996. The tandem repeat domain
in the Listeria monocytogenes ActA protein controls the rate
of actin-based motility, the percentage of moving bacteria and the
localization of VASP and profilin. J. Cell Biol. 135(3):
647-660 |
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Smith, G.A., D.A. Portnoy. 1997. How the Listeria monocytogenes
ActA protein converts actin polymerization into a motile
force. Trends. Microbiol. 5(7):272-276 |
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Enquist, L.W., P.J. Husak, B.W. Banfield, G.A. Smith. 1998. Infection
and spread of alphaherpesviruses in the nervous system. Adv. Virus
Res. 51: 237-347 |
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Smith, G.A., L.W. Enquist. 1999. Construction and transposon
mutagenesis in Escherichia coli of a full-length infectious clone of
pseudorabies virus, an alphaherpesvirus. J. Virol. 73(8): 6405-6414 |
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Smith, G.A., L.W. Enquist. 2000. A self-recombining bacterial
artificial chromosome and its application for analysis of
herpesvirus pathogenesis. Proc. Natl. Acad. Sci. USA. 97(9):
4873-4878 |
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Smith, G.A., S.P. Gross, L.W. Enquist. 2001. Herpesviruses use
bi-directional fast-axonal transport to spread in sensory neurons.
Proc. Natl. Acad. Sci. USA. 98(6): 3466-3470 |
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Tomishima,
M., G.A. Smith, L.W. Enquist. 2001. Sorting and transport of
alpha herpesviruses in axons. Traffic 2: 429-436 |
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Yu, D., G.A. Smith, L.W. Enquist, T. Shenk. 2002. Construction of a self-excisable bacterial
artificial chromosome containing the human cytomegalovirus genome and mutagenesis of the diploid TRL/IRL13 gene. J. Virol. 76(5): 2316-2328 |
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Enquist, L.W., M.J. Tomishima, S.P. Gross, G.A. Smith. 2002. Directional spread of an alpha-herpesvirus
in the nervous system. Vet. Microbiol. 86(1-2): 5-16 |
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Carlén, M., R.M. Cassidy, H. Brismar, G.A. Smith, L.W. Enquist, J. Frisén. 2002. Functional integration of adult-born neurons.
Curr. Biol. 12(7): 606-608 |
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Smith, G.A., L.W. Enquist 2002. Break ins and break outs: viral interactions with the cytoskeleton of mammalian cells. Annu. Rev. Cell Dev. Biol. 18: 135-161 |
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Smith, G.A. 2003. Escherichia coli gets a new virus but it’s nothing to sneeze at. Trends Biotech. 21(3): 106-108 |
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Smith, G.A., L. Pomeranz, S.P. Gross, L.W. Enquist. 2004. Local modulation of plus-end transport targets herpesvirus entry and egress in axons. Proc. Natl. Acad. Sci. USA. 101(45): 16304-16309 |
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Luxton, G.W., S. Haverlock, K.E. Coller, S.E. Antinone, A. Pincetic, G.A. Smith. 2005. Targeting
of herpesvirus capsid transport in axons is coupled to association with specific sets of tegument proteins. Proc. Natl. Acad. Sci. USA. 102(16): 5832-5837 |
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Luxton, G.W., S. Haverlock-Moyns, J.M. Schober, G.A. Smith. 2005. The pseudorabies virus VP1/2
tegument protein is required for intracellular capsid transport. Submitted. |
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Antinone, S.E., G.A. Smith. 2005. Herpesviruses use a vesicular transport mechanism to reach the
distal axon. Manuscript in preparation. |
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Contact
Information:
Greg Smith, Ph.D.
Northwestern University Medical School
Department of Microbiology-Immunology
303 E. Chicago Ave.
Ward 10-105
Chicago, IL 60611 |
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