Jason Smith
Assistant Professor of Microbiology

Email: jgsmith2@u.washington.edu
Phone: (206) 685-6144
Office Location: Health Sciences, J-279a
Campus Box: 357735

Research:

Dr. Smith performed his graduate studies at Harvard University in the laboratory of Dr. James Cunningham. His thesis focused on understanding how conformational changes in the envelope glycoprotein of the retrovirus avian leukosis virus A are linked to entry and infection. As a postdoctoral fellow in the laboratory of Dr. Glen Nemerow at the Scripps Research Institute, Dr. Smith studied the mechanisms of action of innate (e.g., defensins) and adaptive (e.g., neutralizing antibodies) immune effectors in neutralizing human adenovirus infection.

The Smith lab is primarily focused on understanding the role of defensins in antiviral immunity.  Defensins are a class of antimicrobial peptides with broadly acting antibacterialactivity; however, their role in antiviral immunity, particularly for nonenveloped viruses, is less well understood.  Using a variety of approaches from virology, cell biology, biochemistry, structural biology, and genetics, our work is focused on understanding the interaction of defensins with human adenovirus in molecular detail.  We are also interested in using animal models of viral diseases to understand the role of defensins in antiviral immunity in vivo.  Finally, through comparative studies with other nonenveloped viruses such as human papillomavirus and adeno-associated virus, we will determine general principals of defensin-mediated neutralization of nonenveloped virus infection.

A second focus of the Smith lab is the development of antivirals against influenza virus based on a novel cyclic D,L-alpha-peptide scaffold.  In collaboration with M. Reza Ghadiri at the Scripps Research Institute, we have identified a number of peptides that broadly neutralize influenza virus infection at low micromolar concentrations. Ongoing research is focused on understanding the mechanisms by which these compounds neutralize infection, optimization of initial hits through structure-activity relationship studies, identification of additional peptides with novel modes of action, and efficacy and toxicity studies in animal models.

Selected Publications:

Smith, J.G., Wiethoff, C.M., Stewart, P.L., and Nemerow, G.R. (2010). Adenovirus. Curr Top Microbiol Immunol.

Smith, J.G., Silvestry, M., Lindert, S., Lu, W., Nemerow, G.R., and Stewart, P.L. (2010). Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization. PLoS Pathog6, e1000959.

Nguyen EK, Nemerow GR, and Smith JG (2010) Direct evidence from single-cell analysis that human alpha-defensins block adenovirus uncoating to neutralize infection. J Virol, in press.

Silvestry M, Lindert S, Smith JG, Maier O, Wiethoff CM, et al. (2009) Cryo-electron microscopy structure of the adenovirus type 2 temperature sensitive mutant 1 reveals insight into the cell entry defect. J Virol 83:7375-83.

Smith JG, Nemerow GR (2008) Mechanism of adenovirus neutralization by human alpha-defensins. Cell Host Microbe 3: 11-19.

Smith JG, Cassany A, Gerace L, Ralston R, Nemerow GR (2008) Neutralizing antibody blocks adenovirus infection by arresting microtubule-dependent cytoplasmic transport. J Virol 82: 6492-6500.

Smith JG, Cunningham JM (2007) Receptor-Induced Thiolate Couples Env Activation to Retrovirus Fusion and Infection. PLoS Pathogens 3: e198.

Smith JG, Mothes W, Blacklow SC, Cunningham JM (2004) The mature avian leukosis virus subgroup A envelope glycoprotein is metastable, and refolding induced by the synergistic effects of receptor binding and low pH is coupled to infection. J Virol 78: 1403-1410.