BUMC Research Profile<\/strong><\/a><\/p>\nOur laboratory investigates innate and adaptive immunity and microbial pathogenesis, especially in regards to vaccine development.\u00a0 One major aspect of this work centers on the pathogenic Neisseria, Neisseria gonorrhoeae<\/i> and Neisseria meningitidis<\/i>.\u00a0 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.\u00a0 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.\u00a0 Moreover, MAPK signaling events are required for the upregulation of the expression of these markers, as well as production of pro-inflammatory cytokines.<\/p>\n
We are investigating the use of this TLR2 ligand, PorB, as a vaccine adjuvant using classic antigens i.e. OVA, \u00a0and more relevant antigens, i.e. bacterial capsular polysaccharide.\u00a0 We are also comparing the PorB adjuvant activity to other classical and investigative adjuvants including Alum, MF59, CpG DNA and MPL.\u00a0 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).\u00a0 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.\u00a0 Surprisingly, the presence of MyD88 in macrophages seems to be the most essential component needed for this adjuvant activity.\u00a0 Investigations are ongoing in this area.\u00a0\u00a0 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.\u00a0 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.\u00a0 Interestingly, if MyD88 is conditionally KO\u2019d in macrophages, these germinal center findings are abrogated.\u00a0 Using these same mice we have found that PorB induces both Th1 and Th2 type responses as determined by cytokine profiles and IgG isotypes.\u00a0 PorB induced a greater breadth of response in this regard as compared to Alum, MF59 and MPL.\u00a0 We are currently investigating the mechanisms behind these findings.<\/p>\n
We have also begun a systems immunologic analysis of the adjuvant activity of PorB.\u00a0 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.\u00a0 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).\u00a0 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.<\/p>\n
A significant new set of studies currently being performed win 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.\u00a0 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.\u00a0 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.\u00a0 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.\u00a0 These studies are currently on going.<\/p>\n
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Professor of Medicine, Associate Professor of Microbiology BS, SUNY\/Binghamton MD, SUNY\/Upstate Medical Center, Syracuse BUMC Research Profile Our laboratory investigates innate and adaptive immunity and microbial pathogenesis, especially in regards to vaccine development.\u00a0 One major aspect of this work centers on the pathogenic Neisseria, Neisseria gonorrhoeae and Neisseria meningitidis.\u00a0 We have found that the major […]<\/p>\n","protected":false},"author":1270,"featured_media":0,"parent":10,"menu_order":31,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/pages\/28"}],"collection":[{"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/users\/1270"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/comments?post=28"}],"version-history":[{"count":18,"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/pages\/28\/revisions"}],"predecessor-version":[{"id":2628,"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/pages\/28\/revisions\/2628"}],"up":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/pages\/10"}],"wp:attachment":[{"href":"https:\/\/www.bumc.bu.edu\/immunology\/wp-json\/wp\/v2\/media?parent=28"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
![\"Wetzler\"](\"http:\/\/www.bumc.bu.edu\/microbiology\/files\/2002\/03\/Wetzler2-150x150.gif\" "\\"Wetzler\\"")
Professor of Medicine, Associate Professor of Microbiology<\/h3>\n