Christopher M. Wiethoff, Ph.D.
Assistant Professor

Ph.D. University of Kansas

Virologist

Virus Cell Entry and Innate Immunity

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The innate immune system is the first line of defense against many pathogens including viruses.   This innate immune response to viral infection prevents the replication and spread of viruses and directs the adaptive immune response which ultimately clears the viral infection.  Using adenovirus as a model, my lab is identifying cellular and viral molecules  which mediate the innate immune response to viruses as they enter cells.  Since adenovirus is known to induce a very rapid proinflammatory response upon entering cells, our first goal has been to better define the mechanisms adenovirus uses to enter cells.  Initially we have used biochemical and biophysical approaches to define the mechanism which adenovirus uses to cross cell membranes during cell entry.  In particular, we have demonstrated that the adenovirus capsid protein VI ruptures endosomal membranes to release the virus into the cytoplasm.  More recently we have  used this information to define how the virus is sensed by cells to initiate an innate proinflammatory response.  Specifically, we have determined that viral rupture of endosomal membranes during cell entry is sensed by cells as a “danger” signal which induces the formation of a signaling complex known as the inflammasome.  Inflammasome formation is necessary for the release of several proinflammatory cytokines known to contribute to adenovirus-induced inflammation. 

We are also exploiting  our knowledge of the influence of adenovirus cell entry on  the innate immune response to design improved adenovirus vectors for use in genetic vaccines.  The  vectors could ultimately be used in vaccines for a variety of pathogens such as tuberculosis or HIV.


Selected Publications

Maier O, Wiethoff C.M. (2010) N-terminal alpha-helix-independent membrane interactions facilitate adenovirus protein VI induction of membrane tubule formation. Virology. In press

Smith, J.G., Wiethoff, C.M., Stewart, P.L., Nemerow G.R. (2010) Adenovirus.  Current Topics in Microbiology and Immunology.  343:In press

Maier, O., Galan, D.L. Wodrich, H. and Wiethoff C.M. (2010)  An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature. Virology.  402(1):  11-9.

Wodrich, H., Henaff, D., Jammart, B. Segura-Morales, C. Coux, O. Ruzsic, Z., Wiethoff, C.M. and Kremer E. J. (2010) A capsid encoded PPxY-motif facilitates adenovirus entry.  Plos Pathogens 6(3):e1000808.

Silvestry M, Lindert S, Smith JG, Maier O, Wiethoff C.M., Nemerow GR, Stewart PL. (2009) Cryo-electron microscopy structure of adenovirus type 2 temperature-sensitive mutant 1 reveals insight into the cell entry defect.J Virol. 83(15):7375-83. Epub 2009 May 20.

Lai CY, Wiethoff C.M., Kickhoefer VA, Rome LH, Nemerow GR. (2009) Vault nanoparticles containing an adenovirus-derived membrane lytic protein facilitate toxin and gene transfer. ACS Nano. 3(3):691-9.

Horne WS, Wiethoff C.M., Cui C, Wilcoxen KM, Amorin M, Ghadiri MR, Nemerow GR. (2005) Antiviral cyclic d,l-alpha-peptides: Targeting a general biochemical pathway in virus infections. Bioorg Med Chem. 13(17):5145-53. 

Wiethoff C.M., Wodrich H, Gerace L, Nemerow GR. (2005) Adenovirus protein VI mediates membrane disruption following capsid disassembly. J Virol. 79(4):1992-2000. 

Search PubMed for a complete listing of Chris Wiethoff's publications

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