Using Genomics and Proteomics to Halt Infectious Diseases
Dr. Guy Palmer and his colleagues are using genomics and proteomics to identify new targets for vaccine development with the goal of preventing infectious diseases.
Key to vaccine development is the identification of specific sites within microbial proteins, termed epitopes, that bind surface receptors on lymphocytes and stimulate their proliferation. Traditional approaches to epitope identification were based on either knowing the function of the microbial protein, such as a ligand for binding to host cells, or its location within the microbe, for example, on the outer membrane surface.
While these approaches resulted in vaccines against numerous infectious agents, many important pathogens of animals and humans remain uncontrolled due to poor vaccine efficacy. A proteomic approach, however, can work in "reverse"- that is the responding lymphocyte or antibody secreted by the lymphocyte from an immune animal is used to select the pathogen epitope without bias as to its function or location. While this strategy itself is not new, it is the availability of linked genomics and proteomics that makes it technically feasible.
CD4+ T lymphocytes, cells that help B lymphocytes make antibody to bind the pathogen and that activate phagocytic cells to engulf the antibody-coated pathogen, bind to only a small stretch of the protein, approximately 10-20 amino acids. To search for this "needle in the haystack" among the 1 million or so amino acids in a bacterium, the full set of proteins are separated by molecular size and then tested for stimulation of T lymphocytes from immune animals. Those that stimulate T cell proliferation, still an unknown mixture, are characterized by trypsin digestion followed by mass spectrometry. The key to actually identifying the proteins is to map these actual tryptic fragments back to those predicted by analysis of the complete genome sequence of the bacterium. The identified protein or proteins can then be tested as a vaccine to confirm that the predicted T cell response is induced.
Implementing this strategy requires interdisciplinary expertise in microbial structure, immunology, genomics, and proteomics. At Washington State University , Dr. Palmer, immunologist Dr. Wendy Brown, molecular genomicist Dr. Kelly Brayton, and mass spectroscopy expert Dr. Bill Siems are using this approach in vaccine development against the blood-borne animal pathogen Anaplasma marginale. In addition to addressing a need for a vaccine against this specific animal pathogen, this research effort is leading new approaches to improve the safety and efficacy of vaccines, including agents at risk for use as bioterrorism agents.
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