Associate Professor and Distinguished Teacher, Emeritus
PhD, 1978, State University of New York at Buffalo
The specific or adaptive immune response to intracellular pathogens (viruses, intracellular bacteria) and tumors starts with predictable events that target dangerous proteins for recognition and removal. In the cytoplasm, pathogen or tumor proteins are directed to the immune system by a series of antigen processing events. Antigenic peptides from degraded pathogen or tumor proteins are shuttled into the endoplasmic reticulum and embedded non-covalently in major histocompatibility I (MHC-I) proteins. The peptide-MHC complex is then transited to the cell surface; the displayed complex is exposed to T cells for initiation of a protective immune response.
We and others have engineered covalently linked peptide-MHC complexes called single-chain trimers (SCT) that can be expressed on the cell surface without the need for antigen processing. SCTs function similarly to native peptide-MHC complexes. First, expressed SCT complexes interact with the same antibodies and T cells that interact with normal peptide-MHC complexes. Second, the SCT is capable of initiating an immune response. Because we can select and immobilize the antigen peptide, the SCT can efficiently focus the immune response to any desired antigen peptide. We have further modified the SCT to include an additional covalent modification, a disulfide bond we termed a disulfide trap (dt), near the end of the peptide. The resulting dtSCT enhances peptide binding in vitro.
The dtSCT constructs will be used as DNA vaccines to generate directed immune responses in vivo without the need to consider antigen processing limitations, and with the further benefit of not exposing the host to pathogens or pathogen components. We will initially target immune responses to model proteins and then to individual antigenic proteins from intracellular pathogens or tumors. We plan to develop and test model vaccines in mice to important human pathogens such as influenza virus and Listeria.
- Madigan, M.T., Martinko, J.M., Stahl, D.A. and Clark, D.P. 2010. Brock Biology of Microorganisms, 13th edition, Pearson Benjamin-Cummings, San Francisco.
Madigan, M.T., Martinko, J.M., Dunlap, P.V. and Clark, D.P. 2009. (published February, 2008) Brock Biology of Microorganisms, 12th edition, Pearson Benjamin-Cummings, San Francisco. ISBN 0-13-2232460-1.
Madigan, M.T. and Martinko, J.M. 2006. (published February, 2005). Brock Biology of Microorganisms, 11th edition. Pearson Prentice Hall, Upper Saddle River, NJ. ISBN 0-13-144329-1.
Truscott, S.M., Wang, X., Lybarger, L., Biddison, W.E., McBerry, C., Martinko, J.M., Connolly, J.M., Linette, G.P., Fremont, D.H., Hansen, T.H. and Carreno, B.M. 2008. Human major histocompatibility complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides. J. Biol. Chem. 283:7480-7490. PubMed link
Truscott, S.M., Lybarger, L., Martinko, J.M., Mitaksov, V.E., Kranz, D.M., Connolly, J.M., Fremont, D.H., and Hansen, T.H. 2007. Disulfide bond engineering to trap peptides in the MHC class I binding groove. J. Immunol. 178:6280-89. PubMed link