Thomas R. Kozel, Ph.D.
|
|
Research Interests:
Studies in the Kozel laboratory examine opportunistic fungal infections that are important in the immunocompromised patient. Patients who are immunosuppressed by cancer chemotherapy or the loss of cellular immunity due to progression of HIV infection to AIDS are highly susceptible to life-threatening infections by fungi such as Cryptococcus neoformans and Candida albicans. These studies focus on the capsular polysaccharide of Cryptococcus neoformans and the outer layer of mannan on Candida albicans. Research questions include the biological functions of these surface structures and their interactions with serum proteins such as antibodies, mannan binding lectin and proteins of the complement system. Experimental approaches emphasize structural chemistry of polysaccharides and molecular immunology with particular emphasis on use of monoclonal antibodies. Training opportunities for graduate students and postdoctoral fellows include studies of fungal pathogenesis, polysaccharide immunochemistry, studies of protein-polysaccharide interaction (including molecular modeling in collaboration with the laboratory of William Welch) and the production and characterization of monoclonal antibodies.
An example of the molecular immunology approach to structure-function studies with fungal surface antigens is illustrated in the figure below. Cells of Cryptococcus neoformans that have very large polysaccharide capsules were incubated with two distinct monoclonal antibodies. The antibodies are reactive with two different epitopes found on the capsular polysaccharide. One antibody produces a prominent annular rim (“rim” pattern) around the surface of the capsule; the second antibody produces a “puffy” pattern that is visible throughout the capsule. Importantly, the two antibodies have strikingly different biological activities. The antibody producing the rim pattern is i) a better agglutinator of whole cells, ii) a better activator of the classical complement pathway, iii) more opsonic for phagocytosis of the yeast by macrophages and iv) protective in a murine model of disseminated cryptococcosis. A determination of the molecular basis for the “rim” vs. “puffy” patterns is currently a major area of study in the Kozel laboratory.
Capsular reaction following incubation of Cryptococcus neoformans yeast cells with i) no antibody (left), ii) mAb 3C2 (“rim pattern”) or iii) mAb 302 (“puffy” pattern). mAbs 3C2 and 302 are monoclonal antibodies that recognize two different epitopes that are expressed in the polysaccharide capsule (See MacGill et al., 2000 below)
Recent publications:
Kozel, T.R., B.C.H. deJong, M. Grinsell, R. S. MacGill, and K. Wall. 1998. Epitope specificity influences the ability of anti-capsular monoclonal antibodies to activate the classical and alternative complement pathways leading to binding of C3 fragments to the Cryptococcus neoformans capsule. Infect. Immun. 66:1538-1546.
Kozel, T.R., R.S. MacGill, and K.K. Wall. 1998. Bivalency is required for anti-capsular monoclonal antibodies to suppress activation of the alternative complement pathway by the Cryptococcus neoformans capsule. Infect. Immun. 66:1547-1553.
Zhang, M.X., and T.R. Kozel. 1998. Mannan-specific IgG antibodies in normal human serum accelerate binding of C3 to Candida albicans via the alternative complement pathway. Infect. Immun. 66:4845-4850.
Monari, C., T.R. Kozel, A. Casadevall, D. Pietrella, B. Palazetti, and A. Vecchiarelli. 1999. B7 co-stimulatory ligand regulates development of the T cell response to Cryptococcus neoformans. Immunology. 98:27-35.
Pietrella, D., C. Monari, C. Retini, B. Palazzetti, T.R. Kozel, and A. Vecchiarelli. 1999. Human immunodeficiency virus type 1 envelope glycoprotein gp120 induces development of a dominant T helper Type 2 response to Cryptococcus neoformans. AIDS. 13:2197-2207.
MacGill, T.C., R.S. MacGill, A. Casadevall, and T.R. Kozel. 2000. Biological correlates of capsular (quellung) reactions of Cryptococcus neoformans. J. Immunol. 164:4835-4842.
Retini, C., D. Pietrella, C. Monari, T.R. Kozel, and A. Vecchiarelli. 2000. Communication between T lymphocytes and monocytes via DC40/CD40L provides a potential mechanism for the induction of a lymphoproliferative response and killing of Cryptococcus neoformans in vitro. Eur. J. Immunol. 30:1385-1393.
MacGill, T.C., R.S. MacGill, and T.R. Kozel. 2000. Capsular reactions of Cryptococcus neoformans with polyspecific and oligospecific polyclonal anticapsular antibodies. Infect. Immun. Infection and immunity 2001, Feb.;69(2) 1189-1191
MacGill, T.C., R.S. MacGill, A. Casadevall, and T.R. Kozel. 2000. Biological correlates of capsular (quellung) reactions of Cryptococcus neoformans. J. Immunol. 164:4835-4842
MacGill, T.C., R.S. MacGill, and T.R. Kozel. 2001. Capsular reactions of Cryptococcus neoformans with polyspecific and oligospecific polyclonal anticapsular antibodies. Infect. Immun. 69:1189-1191
Han, Y., T.R. Kozel, M.X. Zhang, R.S. MacGill, M.C Carroll, and J.E. Cutler. 2001. Complement is essential for protection by an IgM and an IgG3 monoclonal antibody against experimental disseminated candidiasis. J. Immunol. 167:1550-1557
Grinsell, M., L.C. Weinhold, J.E. Cutler, Y. Han, and T.R. Kozel. 2001. In vivo clearance of glucuronoxylomannan, the major capsular polysaccharide of Cryptococcus neoformans: a critical role for tissue macrophages. J. Infect. Dis. 184:479-487.