Lee M. Wetzler, M.D.
Associate Professor of Medicine and Microbiology
B.S. SUNY/Binghamton
M.D. SUNY/Upstate Medical Center, Syracuse
My laboratory is interested in bacterial pathogenesis and the generation of protective immune responses. Our work mainly centers on the pathogenic neisseria, Neisseria gonorrhoeae and Neisseria meningitidis. We have been using the major outer membrane protein of the neisseria, termed porins, as potential vaccine candidates. We are currently involved in a collaboration with the Rockefeller University and the NIH in bringing to human trails a potential anti-gonococcal vaccine utilizing the gonococcal porins inserted in liposomes.
A unique property of these porins is their ability to act as immune stimulators and augment the immune response to poorly immunogenic substances. Their adjuvant activity is likely due to their ability to act as B cell mitogens, increasing the expression of the T cell costimulatory factor, B7-2 on the surface of B cells (and likely other antigen presenting cells). Neisserial porin is also able to induce maturation of dendritic cells and improves their ability to present antigen to T cells. We are also investigating the signal transduction events induced by the porins. We have found that Neisserial poirns can induce protein tyrosine kinase activity and NF-kappaB nuclear translocation, both essential in their ability to induce B7-2 and class II MHC expression. Porin can also induce MAPKK (MEK) activity to elicit phosphorylation and activation of MAPK1/2 (Erk1/2), but not p38 or jnk MAPKs. We have preliminary data that suggests that the majority of these effects is due to an interaction of Neisserial porin wihtt eh pattern recognition recpeptor TLR2.
More recent data demonstrates that these porins also seem to effect the susceptibility of activated B cells to apoptosis. We are currently investigating the mechanism of this effect and have shown that it is due to an interaction of the porins with eukaryotic cell mitochondria and stabilization of the mitcochondrial membrane that is normally perturbed by apoptotic stimuli.
Another group of studies we are performing is investigation into the relationship between the immune response to gonococcal porins in patients and partners of patients with gonorrhea and possible protective immunity. We are measuring the T cell response in female partners of men with gonorrhea and relating these findings to whether the female partners in turn get gonorrhea. This is being performed as part of the STD-CRC program project grant that our division has received.
Representative Publications:
- Mackinnon, F.M, Ho, Y., Blake, M.S., Michon, F., Chandraker, A., Sayegh, M.H., and Wetzler, L.M. 1999. The role of B/T costimulatory signals in the adjuvant activity of a conjugate vaccine containing neisserial porin. J. Infect. Dis. 180:755-761.
- Simpson, S.D., Ho, Y, Rice, P.A., and Wetzler, L.M. 1999. T cell responses to neisserial porins in patients with gonococcal disease. J. Infect. Dis. 180:762-773.
- Massari, P. Ho, Y. and. Wetzler,.L.M. 2000. Neisseria meningitidis porin PorB interacts with mitochondria and protects cells from apoptosis Proc. Natl. Acad. Sci. 97:9070-9075.
- Wedege, E., Bolstad, K., Wetzler, L.M., and Guttormsen, H-K. 2000. IgG antibody activity against meningococcal class 1 and 3 outer membrane proteins in patient sera: comparison between immunoblot and ELISA analysis J. Imm. Methods. 244:9-15.
- Massari, P. .and Wetzler, L.M., Effect of Neisserial Porins on Host Immune Response, EOS Rivista di Immunologia ed Immunopharmacologia, 20:49-53, 2000.
- Bhasin, N., Ho, Y., and Wetzler, L.M. 2001. Neisseria meningitidis lipopolysaccharide modulates the specific humoral immune repsonse to Neisserial porins but has no effect on porin-inuced upregulation of costimulatory ligand B7-2 Infection and Immunity. 69:5031-5036.
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