Lee M. Wetzler, M.D.
Professor of Medicine
Associate Professor of Microbiology
M.D. SUNY/Upstate Medical Center, Syracuse
Dr. Wetzler’s laboratory investigates innate and adaptive immunity and microbial pathogenesis, especially in regards to vaccine development. One major aspect of this work centers on the pathogenic Neisseria, Neisseria gonorrhoeae and Neisseria meningitidis. He has found that the major outer membrane protein of these organisms, the Neisserial porin PorB, can work as an immune adjuvant due to it recognition by the pattern recognition receptor TOLL-like receptor (TLR) 2. He has found that antigen presenting cells, including B cells, dendritic cells and macrophages, are activated by PorB in a TLR2 , TLR1 and MyD88 dependent manner, inducting upregulation of class II MHC, costimulatory molecule CD86 and other markers of activation. Moreover, MAPK signaling events are required for the upregulation of the expression of these markers, as well as production of pro-inflammatory cytokines. Moreover, using an in vivo peritoneal mouse model of inflammation, we have shown that both PorB and intact N. meningitidis induce a significant cellular infux and pro-inflammatory cytokine production, which is also TLR2 dependent. However, we also found that mast cells are activated during this process, which may be in a TLR2 independent manner, along with a significant influx of eosinophils, indicative of induction of a TH2 type cellular response. Studies are continuing to investigate the mechanisms of these phenomena.
We are also investigating the use of this TLR2 ligand, PorB, as a vaccine adjuvant using classic antigens like OVA and more relevant antigens like bacterial capsular polysaccharide. This work has also been extended to investigate the adjuvant activity and mechanism of immune stimulation of the B subunit of cholera toxin. We have found that CTB induces antigen presenting cell stimulation via the lipid raft ganglioside GM1 via induction of a cell-signaling program ending in NF-kB and CREB activation and gene transcription. This work is still on going.
Finally, a new major thrust of the Wetzler lab is investigating the immune response and natural history of Francisella tularensis pulmonary infection in mice and using this data to aid in developing vaccines towards this potential bio-terrorist agent. We have found that using PorB as an adjuvant and Francisella LPS as an atigne, we can enhance protection in these mice, which is likely due to induction of antibodies and improved immunity (potentially both innate and adaptive immunity. It appears that induction of IL-1beta may be more associated with survival bith during natural infection and after vaccination, while IL-6 and IL-17 may have the opposite effect, being more associated with death after pulmonary infection. Finally we have recently found that induction of bronchial associated lymphoid tissue (BALT) after vaccaitnion also appears to be associated with protection. These iBALT structures are long lasting and may be due to persistent antigen stimulation, which we are currently investigating.
1. Massari, P. Visintin, A., Gunawardana, J., Halmen, K., King, C.A., Golenbock, D. T., and Wetzler, L.M. 2006 Meningococcal porin PorB binds to TLR2 and requires TLR1 for signaling, J. Immunol., 176:2373-80
2. Burke, J.M., Ganley-Leal, L. M., Khatri, A., and Wetzler, L. M. 2007 Neisseria meningitidis PorB, a TOLL-like receptor 2 ligand, induces an antigen-specific eosinophil recall response: Potential adjuvant for helminth vaccines?, J. Immuno. 179:3222-30
3. Macleod, H.M. and Wetzler, L.M., 2007, T cell activation by TLRs: a role for TLRs in the adaptive immune response, Sci STKE. Sep 4;2007(402):pe48.
4. Chiavolini, D., Allroy, J., King, C.A., Jorth, P., Weir, S., Madico, G., Murphy, J. and Wetzler, L.M., 2008, Identification of immunologic and pathologic parameters of death versus survival in respiratory tularemia. Infect Immun. 76:486-96
5. Macleod, H.M., Bhasin, N., and Wetzler, L.M., 2008, Role of protein tyrosine kinase and Erk1/2 activities in the Toll-like receptor 2-induced cellular activation of murine B cells by neisserial porin. Clin Vaccine Immunol. 15:630-7
6. Chiavolini D., Weir S., Murphy J.R., Wetzler L.M., 2008, Neisseria meningitidis PorB, a Toll-like receptor 2 ligand, improves the capacity of Francisella tularensis lipopolysaccharide to protect mice against experimental tularemia. Clin Vaccine Immunol. 15(9):1322-9