Blake Wiedenheft, Assistant Professor
Immunology & Infectious Diseases
Effective clearance of an infection requires that the immune system rapidly detects and neutralizes invading parasites, while strictly avoiding self-antigens that would result in autoimmunity. The sophisticated cellular machinery and signaling pathways that coordinate an effective immune response have generally been considered to be properties of the eukaryotic immune system. However, a surprisingly sophisticated adaptive immune system that relies on small RNAs for sequence specific targeting of invading parasites has recently been discovered in bacteria and archaea. Central to this immune system is a diverse family of DNA repeats called CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats). These repetitive loci serve as molecular vaccination cards that maintain a genetic record of all prior encounters with foreign transgressors (i.e. viruses and plasmids). The acquisition of foreign DNA and sequence-specific interference is mediated by a diverse set of CRISPR-associated (Cas) proteins that are encoded in gene clusters that flank each CRISPR locus. Phylogenetic analyses preformed using a universally conserved cas gene (Cas1) have identified several distinct versions of the CRISPR system that each consist of a unique set of 4-10 cas genes. In each of these systems, the CRISPR locus is transcribed and the long primary transcripts are processed into a library of short CRISPR-derived RNAs (crRNAs) that each contain a unique sequence complementary to a foreign nucleic acid challenger. Each crRNA is packaged into a large, multi-subunit surveillance complex that patrols the intracellular environment and ‘silences’ invading foreign nucleic acid targets (Fig. 1).
The general steps required for adaptive immunity in bacteria and archaea have been identified, however the mechanisms of foreign nucleic acid recognition, new sequence acquisition and RNA-guided interference are not understood. The Wiedenheft laboratory uses molecular biology to engineer model microbes for functional and structural interrogation of the molecular machines that coordinate an effective immune response.
Interested in joining the Wiedenheft lab? Please send an email to Blake Wiedenheft (bwiedenheft /at\ gmail /d0t\ com), stating your research interests and experience. Please attach a CV describing your educational accomplishments, publication record, and contact information of your references.
- B.S. Montana State University, Bozeman, MT; 1998; Biology
- Ph.D. Montana State University, Bozeman, MT; 2006; Microbiology
- Postdoctoral Fellow. University of California, Berkeley, CA; 2007-20012; Molecular Biology
Sashital, D.G., Wiedenheft, B., and Doudna, J.A. (2012). Mechanism of foreign DNA selection in a bacterial adaptive immune system. under review.
Wiedenheft, B., Sternberg, S.H., and Doudna, J.A. (2012). RNA-guided genetic silencing systems in bacteria and archaea. Nature Insight, in press.
Wiedenheft, B., Lander, G.C., Zhou, K., Jore, M.M., Brouns, S.J.J., van der Oost, J., Doudna, J.A., and Nogales, E. (2011a). Structures of the RNA-guided surveillance complex from a bacterial immune system. Nature 477, 486-489.
Jore, M.M., Lundgren, M., van Duijn, E., Bultema, J.B., Westra, E.R., Waghmare, S.P., Wiedenheft, B., Pul, U., Wurm, R., Wagner, R., et al. (2011). Structural basis for CRISPR RNA-guided DNA recognition by Cascade. Nat Struct Mol Biol 18, 529-536.
Wiedenheft, B., van Duijn, E., Bultema, J., Waghmare, S., Zhou, K., Barendregt, A., Westphal, W., Heck, A., Boekema, E., Dickman, M., et al. (2011b). RNA-guided complex from a bacterial immune system enhances target recognition through seed sequence interactions. Proc Natl Acad Sci U S A 108, 10092-10097.
Haurwitz, R.E., Jinek, M., Wiedenheft, B., Zhou, K., and Doudna, J.A. (2010). Sequence- and structure-specific RNA processing by a CRISPR endonuclease. Science 329, 1355-1358.
Wiedenheft, B., Zhou, K., Jinek, M., Coyle, S.M., Ma, W., and Doudna, J.A. (2009). Structural basis for DNase activity of a conserved protein implicated in CRISPR-mediated antiviral defense. Structure 17, 904–912.
Wiedenheft, B., Flenniken, M.L., Allen, M.A., Young, M., and Douglas, T. (2007). Bioprospecting in high temperature environments; application of thermostable protein cages. Soft Matter 3, 1091-1098.
Ortmann, A., Wiedenheft, B., Douglas, T., and Young, M. (2006). Hot Archaeal Viruses Reveal Deep Connections. Nature Reviews Microbiology 4, 520-528.
Wiedenheft, B., Mosolf, J., Willits, D., Yeager, M., Dryden, K.A., Young, M., and Douglas, T. (2005). An archaeal antioxidant: Characterization of a Dps-like protein from Sulfolobus solfataricus. Proceedings of the National Academy of Sciences of the United States of America 102, 10551-10556.
Wiedenheft, B., Stedman, K., Roberto, F., Willits, D., Gleske, A.K., Zoeller, L., Snyder, J., Douglas, T., and Young, M. (2004). Comparative genomic analysis of hyperthermophilic archaeal Fuselloviridae viruses. Journal of Virology 78, 1954-1961.