Paula B Kavathas PhD
Professor of Laboratory Medicine, of Genetics, of Immunobiology and of Molecular, Cellular, and Developmental Biology; Associate Chair for Research; Director, Science Education Outreach Program
Gene Regulation; Immunology; Molecular Cellular Entities; Receptors; Structure or Function (Health or Safety or Medical); Transgenic Animals
Our lab studies an important immune cell coreceptor called CD8 and host-pathogen interaction with Chlamydia trachomatis, an obligate intracellular bacteria. The human and chimpanzee CD8B gene has acquired new exons that lead to isoforms with different cytoplasmic tails. We are determining functional relevance with potential applications to immunotherapy. For the Chlamydia project we are examining the mechanisms by which host cells respond when infected.
Extensive Research Description
Gene Regulation: We created transgenic animals with pieces of human DNA from the human CD8 gene complex (alpha and beta genes) and were able to obtain correct developmental expression of the genes. To localize regulatory elements, we performed sequence analysis, DNase I hypersensitivity mapping, and MAR (matrix attachment region) analysis. We identified several striking regions and are performing further transgenic and knockout studies to firmly establish the presence of regulatory elements. Structure/Funtion Analysis: The CD8 protein interacts with ligands on the outside of the cell (i.e. MHC class I) and with molecules on the inside of the T cell (i.e. tyrosine kinase p56lck, LAT). It also functions as a coreceptor with the T cell receptor forming a complex with MHC class I. Our goal is to understand in molecular terms how the different protein interactions occur and if there are differences between homo (a/a) vs. heterodimeric (a/b) forms of CD8. Taking advantage of crystallographic information, we perform mutational analysis and create models of how the proteins interact. Immune Response to Chlamydia Trachomatis (Ct): Ct is the most common cause of bacterial sexually transmitted disease (STD) worldwide and of ocular trachoma in developing countries. We are characterizing T cell responses to the major outer membrane protein (MOMP) of Ct, a good vaccine candidate. Using special reagents called tetramers, we were able to detect MOMP-specific T cells in the peripheral blood of infected individuals at frequencies that are significant (0.01-0.20% of CD8+ T cells). We plan to continue to characterize these cells with regard to homing receptors and function and will determine their role in immunity to Ct.