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.
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Professor, Microbiology, Boston University School of Medicine
- Active Staff Privileges, Infectious Diseases, Medicine, Boston Medical Center
- State University of New York Upstate Medical University, MD
- State University of New York at Binghamton, BS
- Published on 4/7/2017
Reiser ML, Mosaheb MM, Lisk C, Platt A, Wetzler LM. The TLR2 Binding Neisserial Porin PorB Enhances Antigen Presenting Cell Trafficking and Cross-presentation. Sci Rep. 2017 Apr 07; 7(1):736. PMID: 28389664.
- Published on 3/3/2017
Mosaheb MM, Reiser ML, Wetzler LM. Toll-Like Receptor Ligand-Based Vaccine Adjuvants Require Intact MyD88 Signaling in Antigen-Presenting Cells for Germinal Center Formation and Antibody Production. Front Immunol. 2017; 8:225. PMID: 28316602.
- Published on 8/5/2016
Wetzler LM, Feavers IM, Gray-Owen SD, Jerse AE, Rice PA, Deal CD. Summary and Recommendations from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop "Gonorrhea Vaccines: the Way Forward". Clin Vaccine Immunol. 2016 Aug; 23(8):656-63. PMID: 27335384.
- Published on 7/1/2016
Toussi DN, Wetzler LM, Liu X, Massari P. Neisseriae internalization by epithelial cells is enhanced by TLR2 stimulation. Microbes Infect. 2016 Oct; 18(10):627-638. PMID: 27373686.
- Published on 1/6/2016
Xu F, Reiser M, Yu X, Gummuluru S, Wetzler L, Reinhard BM. Lipid-Mediated Targeting with Membrane-Wrapped Nanoparticles in the Presence of Corona Formation. ACS Nano. 2016 Jan 26; 10(1):1189-200. PMID: 26720275.
- Published on 12/23/2015
Islam EA, Shaik-Dasthagirisaheb Y, Kaushic C, Wetzler LM, Gray-Owen SD. The reproductive cycle is a pathogenic determinant during gonococcal pelvic inflammatory disease in mice. Mucosal Immunol. 2016 Jul; 9(4):1051-64. PMID: 26693700.
- Published on 8/1/2015
Massari P, Gunawardana J, Liu X, Wetzler LM. Correction for Massari et al., meningococcal porin PorB prevents cellular apoptosis in a Toll-like receptor 2- and NF-?B-independent manner. Infect Immun. 2015 Aug; 83(8):3339. PMID: 26157088.
- Published on 2/1/2015
Barlam TF, Morgan JR, Wetzler LM, Christiansen CL, Drainoni ML. Antibiotics for respiratory tract infections: a comparison of prescribing in an outpatient setting. Infect Control Hosp Epidemiol. 2015 Feb; 36(2):153-9. PMID: 25632997.
- Published on 12/24/2014
Kramer CD, Weinberg EO, Gower AC, He X, Mekasha S, Slocum C, Beaulieu LM, Wetzler L, Alekseyev Y, Gibson FC, Freedman JE, Ingalls RR, Genco CA. Distinct gene signatures in aortic tissue from ApoE-/- mice exposed to pathogens or Western diet. BMC Genomics. 2014; 15:1176. PMID: 25540039.
- Published on 12/19/2013
Kattner C, Toussi DN, Zaucha J, Wetzler LM, Rüppel N, Zachariae U, Massari P, Tanabe M. Crystallographic analysis of Neisseria meningitidis PorB extracellular loops potentially implicated in TLR2 recognition. J Struct Biol. 2014 Mar; 185(3):440-7. PMID: 24361688.
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