Lee M. Wetzler, MD

Our 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. We have 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. We have 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.

We are investigating the use of this TLR2 ligand, PorB, as a vaccine adjuvant using classic antigens i.e. OVA, and more relevant antigens, i.e. bacterial capsular polysaccharide. We are also comparing the PorB adjuvant activity to other classical and investigative adjuvants including Alum, MF59, CpG DNA and MPL. We have shown that PorB adjuvant activity is absolutely MyD88 dependent and also largely dependent on the presence of TLR2 (even though there is still some adjuvant activity in TLR2 KO mice). Utilizing conditional KO mice (using the Cre-Lox system) we have discerned that MyD88 signaling in B cells, Dendritic Cells (DC) and Macrophages are essential for the PorB adjuvant activity. Surprisingly, the presence of MyD88 in macrophages seems to be the most essential component needed for this adjuvant activity. Investigations are ongoing in this area. Moreover, we have shown that PorB can enhance both antigen uptake and antigen presenting cell trafficking (especially DCs and macrophages) and these effects are mainly TLR2 dependent. We have recently begun investigating the effect of PorB on germinal center formation and have found that this molecule is extremely potent in inducting germinal centers and proliferating B cells. Interestingly, if MyD88 is conditionally KO’d in macrophages, these germinal center findings are abrogated. Using these same mice we have found that PorB induces both Th1 and Th2 type responses as determined by cytokine profiles and IgG isotypes. PorB induced a greater breadth of response in this regard as compared to Alum, MF59 and MPL. We are currently investigating the mechanisms behind these findings.

We have also begun a systems immunologic analysis of the adjuvant activity of PorB. We have found that PorB induces a genetic program consisting of genes and gene sets needed for immunoglobulin synthesis and cellular proliferation after only one or two immunizations as opposed to a greater number of immunizations of antigen alone to induce a similar response. We are still investigating the genes induced and shall compare these results to results obtained with other adjuvants (both TLR dependent and independent) to determine if these results can be used to correlate with different responses induced by various adjuvants (i.e. Th types, IgG isotypes etc., as mentioned above). This also revealed that PorB can induce certain profiles of micro RNAs that may also be associated with its immune stimulating properties and we are in the midst of studies to further address these interesting findings.

A significant new set of studies currently being performed in collaboration with Dr. Scott Gray-Owen at the University of Toronto is the examination of a new murine model for gonococcal infections and the use of this model to examine potential anti-gonococcal vaccine candidates. Dr. Gray-Owen has developed transgenic mice that express human gonococcal adhesins and other molecules that enhance gonococcal pathogenesis, that are normally lacking in mice. These include CEACAMs, complement binding proteins and iron binding proteins. These mice mimic human infection to a much greater extent as compared to wild type mice, leading to a superior model to both study gonococcal pathogenesis and immunity. We have been able to demonstrate that at early time points more inflammation and cytokine induction occurs in these transgenic mice as opposed to other commonly used models, demonstrating that these previously used models my not be the best approach to study gonococcal infections. These studies are currently on going.

Graduate Faculty (Primary Mentor of Grad Students)
Boston University School of Medicine, Division of Graduate Medical Sciences


Professor
Boston University School of Medicine
Microbiology


Active Staff Privileges
Boston Medical Center
Medicine
Infectious Diseases



BOSTON UNIVERSITY INFLAMMATORY DISORDERS TRAINING GRANT
09/15/2011 - 08/31/2017 (PI)
NIH/National Institute of Allergy & Infectious Diseases
5T32AI089673-05

ROLE OF THE INNATE IMMUNE SYSTEM IN PATHOGEN-INDUCED CHRONIC INFLAMMATION
08/01/2010 - 07/31/2017 (PI of Sub-Project / SP)
PI: Caroline A. Genco, PhD
NIH/National Institute of Allergy & Infectious Diseases
5P01AI078894-05


Gonococcal Vaccine Evaluation in a Humanized Mouse Model
08/02/2017 - 07/31/2021 (PI)
NIH-NIAID
2R01AI103400-05

Neisserial porins and antigen presenting cells
09/01/2016 - 08/31/2020 (PI)
NIH-NIAID
5R01AI040944-20

Gonococcal Vaccine Evaluation in a Humanized Mouse Model
07/17/2013 - 08/01/2017 (PI)
NIH-NIAID
4R01AI103400-04

Gonococcal Vaccine Evaluation in a Humanized Mouse Model
07/17/2013 - 08/01/2017 (PI)
NIH-NIAID
5R01AI103400-03

Neisserial porins and antigen presenting cells
09/01/2015 - 08/31/2016 (PI)
NIH-NIAID
2R56AI040944-19

Neisserial Porins and Antigen Presenting Cells
09/01/2010 - 08/31/2015 (PI)
NIH-NIAID
5R01 AI040944-18

Characterization of a cell free recombinant gonococcal porin
09/01/2014 - 06/30/2015 (PI)
SutroVax, Inc.

Core C - Role of Innate Immune System in Pathogen Induced Chronic Inflammation
08/01/2010 - 06/30/2015 (PI)
Trustees of Boston University NIH-NIAID

Neisserial Porins and Antigen Presenting Cells
09/01/2006 - 08/31/2010 (PI)
NIH-NIAID
5R01 AI040944-13

Immuno - Prophylaxis - Core A: Animals (Tularemia - Murphy)
09/15/2003 - 02/28/2009 (PI)
NIH-NIAID
5 U19 AI056543-05 (A)

Showing 10 of 18 results. Show All Results


Yr Title Project-Sub Proj Pubs
2018 Neisserial porins and antigen presenting cells 5R01AI040944-21 20
2017 Gonococcal Vaccine Evaluation in a Humanized Mouse Model 2R01AI103400-05 1
2017 Neisserial porins and antigen presenting cells 5R01AI040944-20 20
2016 Gonococcal Vaccine Evaluation in a Humanized Mouse Model 4R01AI103400-04 1
2016 Neisserial porins and antigen presenting cells 2R01AI040944-19A1 20
2015 Boston University Inflammatory Disorders Training Grant 5T32AI089673-05 7
2015 Neisserial porins and antigen presenting cells 2R56AI040944-19
2014 Gonococcal Vaccine Evaluation in a Humanized Mouse Model 5R01AI103400-02 1
2014 Neisserial Porins and Antigen Presenting Cells 5R01AI040944-18 20
2014 Animal Core 5P01AI078894-05-7799 22
Showing 10 of 51 results. Show All Results
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.

  1. Francis IP, Islam EA, Gower AC, Shaik-Dasthagirisaheb YB, Gray-Owen SD, Wetzler LM. Murine host response to Neisseria gonorrhoeae upper genital tract infection reveals a common transcriptional signature, plus distinct inflammatory responses that vary between reproductive cycle phases. BMC Genomics. 2018 Aug 22; 19(1):627.View Related Profiles. PMID: 30134832.
     
  2. Islam EA, Anipindi VC, Francis I, Shaik-Dasthagirisaheb Y, Xu S, Leung N, Sintsova A, Amin M, Kaushic C, Wetzler LM, Gray-Owen SD. Specific Binding to Differentially Expressed Human Carcinoembryonic Antigen-Related Cell Adhesion Molecules Determines the Outcome of Neisseria gonorrhoeae Infections along the Female Reproductive Tract. Infect Immun. 2018 Aug; 86(8).View Related Profiles. PMID: 29760215.
     
  3. 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 04 07; 7(1):736.View Related Profiles. PMID: 28389664; DOI: 10.1038/s41598-017-00555-4;.
     
  4. 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.View Related Profiles. PMID: 28316602; DOI: 10.3389/fimmu.2017.00225;.
     
  5. 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; PMCID: PMC4979170; DOI: 10.1128/CVI.00230-16;.
     
  6. 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.View Related Profiles. PMID: 27373686; DOI: 10.1016/j.micinf.2016.06.001;.
     
  7. 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.View Related Profiles. PMID: 26720275; PMCID: PMC4842014; DOI: 10.1021/acsnano.5b06501;.
     
  8. 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.View Related Profiles. PMID: 26693700; PMCID: PMC4915993; DOI: 10.1038/mi.2015.122;.
     
  9. 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.View Related Profiles. PMID: 26157088; PMCID: PMC4496629; DOI: 10.1128/IAI.00627-15;.
     
  10. 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.View Related Profiles. PMID: 25632997; DOI: 10.1017/ice.2014.21;.
     
Showing 10 of 75 results. Show More

This graph shows the total number of publications by year, by first, middle/unknown, or last author.

Bar chart showing 75 publications over 29 distinct years, with a maximum of 6 publications in 2005

YearPublications
19861
19881
19894
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19943
19952
19962
19971
19983
19995
20002
20013
20022
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20056
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20075
20082
20092
20104
20111
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In addition to these self-described keywords below, a list of MeSH based concepts is available here.

Adjuvants
Francisella
Infections Diseases
Innate Immunity
Neisseria
Vaccines
Immunology
STDs
Meningitis
Travel Medicine

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650 Albany St Evans Biomed Research Ctr
Boston MA 02118
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