Thomas Kozel, Ph.D.

Professor
Department of Microbiology and Immunology 320
School of Medicine
University of Nevada
Reno, NV 89557-0320

Office Phone: (775) 784-4124
Howard Medical Sciences, Room 207
Lab Phone: (775) 784-4090
Fax: (775) 327-2332
E-mail: tkozel@medicine.nevada.edu

Specialty Areas:
Pathogenesis, immunotherapy and molecular biology of opportunistic fungal infections with emphasis on yeast infections in patients with AIDS.

Research Interests:

The Kozel laboratory has an interest in the pathogenesis of emerging microbial pathogens and biodefense. Studies are focused in three areas related to the capsules that surround pathogenic bacteria and yeasts. All three areas rely on the production and use of monoclonal antibodies (mAbs) that are reactive with the capsules. First, we are investigating the polysaccharide capsule of the opportunistic yeast Cryptococcus neoformans. Cryptococcosis is a serious opportunistic infection in immunocompromised patients, such as people with AIDS. The capsule is essential to virulence and functions to inhibit phagocytosis of the yeast. We are engaged in structure-function studies that use a molecular immunology approach aimed at understanding how the capsule inhibits phagocytosis and how antibodies to the capsule reverse this phagocytosis-inhibiting function. An example of the molecular immunology approach to structure-function studies with the capsule is illustrated below. Cells of C. neoformans with very large capsules were incubated with four distinct mAbs. Two of these antibodies are protective in a murine model of cryptococcosis; two react with the capsule but fail to protect. The two protective mAbs produce a prominent annular rim (“rim” pattern) around the surface of the capsule. The two non-protective mAbs produce a “puffy” pattern that is visible throughout the capsule. Our studies aim to explain the molecular basis for the two different patterns and the relationship between capsule reaction and the ability of a mAb to protect. Capsule reactions following incubation of Cryptococcus neoformans yeast cells with two mAbs that are protective (mAbs 3C2 and 471) or nonprotective (mAbs 302 and 1326) in a murine model of cryptococcosis.

The second major project examines the polypeptide capsule of Bacillus anthracis. There is a critical need for alternative approaches to prevention and treatment of anthrax. We are studying the extent to which the capsule can be targeted for immunoprotection or immunotherapy. We have been successful in generating mAbs that are reactive with the polypeptide capsule. Using a murine model of pulmonary anthrax, we have demonstrated that targeting the capsule with antibody is a very effective means for prevention of anthrax (see the figure below). Current studies are aimed at optimizing approaches to passive immunization and determining in vitro correlates of protection against pulmonary anthrax. Ability of a mAb that is reactive with the poly-glutamic acid capsule of B. anthracis (mAb F26G3) to protect mice against a pulmonary challenge with B. anthracis spores relative to mice treated with saline (PBS) or an irrelevant isotype control (mAb M600).

The third major project in the Kozel laboratory aims to identify better and faster means for diagnosis of anthrax. The clinical symptoms of inhalation anthrax are non-specific and present a serious diagnostic dilemma. We have found that the capsular polypeptide of B. anthracis is shed into the blood during anthrax. Moreover, we have developed an immunoassay for detection of the capsular antigen. In a murine model of anthrax, assays for capsular antigen closely paralleled bacterial culture of spleen as a measure of bacteremia (see the figure below). Current studies are aimed at optimizing the immunoassay for anthrax antigen and establishing the utility of immunoassay for antigen as a means for early diagnosis of anthrax. Correlation between serum concentrations of the capsular antigen of B. anthracis (poly-glutamic acid – PGA) and bacteremia as shown by splenic colony forming units (CFU) in a murine model of pulmonary anthrax.

Recent publications:

• Gates, M.A., P. Thorkildson and T.R. Kozel. 2004. Molecular architecture of the Cryptococcus neoformans capsule. Mol. Microbiol. 52:13-24.
• Kozel, T.R., W.J. Murphy, S. Brandt, B.R. Blazar, J.A. Lovchik, P. Thorkildson, A. Percival and C.R. Lyons. 2004. mAbs to Bacillus anthracis capsular antigen for immunoprotection in anthrax and detection of antigenemia. Proc. Natl. Acad. Sci. U.S.A. 101:5042-5047.
• Chang, Z.L., Netski, D., Thorklidson, P., and T.R. Kozel. 2006. Binding and internalization of glucuronoxylomannan, the major capsular polysaccharide of Cryptococcus neoformans, by peritoneal macrophages. Infect. Immun. 74:144-151.
• Lillegard, J.B., Sim, R., Thorkildson, P., Gates, M.A., and T.R. Kozel. 2006. Recognition of Candida albicans by mannan binding lectin in vitro and in vivo. J. Infect. Dis. In press.
• Gates, M.A., and T.R. Kozel. 2006. Differential localization of complement component 3 within the capsular matrix of Cryptococcus neoformans. Infect. Immun. In press.