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dc.contributor.authorGregg, K.A.
dc.contributor.authorHarberts, E.
dc.contributor.authorGardner, F.M.
dc.date.accessioned2019-07-15T16:12:10Z
dc.date.available2019-07-15T16:12:10Z
dc.date.issued2017
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85022347345&doi=10.1128%2fmBio.00492-17&partnerID=40&md5=6a57a906e21a6ad7d42a15e206b06ec5
dc.identifier.urihttp://hdl.handle.net/10713/9920
dc.description.abstractAdjuvant properties of bacterial cell wall components like MPLA (monophosphoryl lipid A) are well described and have gained FDA approval for use in vaccines such as Cervarix. MPLA is the product of chemically modified lipooligosaccharide (LOS), altered to diminish toxic proinflammatory effects while retaining adequate immunogenicity. Despite the virtually unlimited number of potential sources among bacterial strains, the number of useable compounds within this promising class of adjuvants are few. We have developed bacterial enzymatic combinatorial chemistry (BECC) as a method to generate rationally designed, functionally diverse lipid A. BECC removes endogenous or introduces exogenous lipid A-modifying enzymes to bacteria, effectively reprogramming the lipid A biosynthetic pathway. In this study, BECC is applied within an avirulent strain of Yersinia pestis to develop structurally distinct LOS molecules that elicit differential Toll-like receptor 4 (TLR4) activation. Using reporter cell lines that measure NF-κB activation, BECC-derived molecules were screened for the ability to induce a lower proinflammatory response than Escherichia coli LOS. Their structures exhibit varied, dose-dependent, TLR4-driven NF-κB activation with both human and mouse TLR4 complexes. Additional cytokine secretion screening identified molecules that induce levels of tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) comparable to the levels induced by phosphorylated hexa-acyl disaccharide (PHAD). The lead candidates demonstrated potent immunostimulation in mouse splenocytes, human primary blood mononuclear cells (PBMCs), and human monocyte-derived dendritic cells (DCs). This newly described system allows directed programming of lipid A synthesis and has the potential to generate a diverse array of TLR4 agonist candidates. IMPORTANCE: There is an urgent need to develop effective vaccines against infectious diseases that continue to be major causes of morbidity and mortality worldwide. Making effective vaccines requires selecting an adjuvant to strengthen an appropriate and protective immune response. This work describes a practical method, bacterial enzymatic combinatorial chemistry (BECC), for generating functionally diverse molecules for adjuvant use. These molecules were analyzed in cell culture for their ability to initiate immune stimulatory activity. Several of the assays described herein show promising in vitro cytokine production and costimulatory molecule expression results, suggesting that the BECC molecules may be useful in future vaccine preparations. Copyright 2017 Gregg et al.en_US
dc.description.sponsorshipThis project was funded by NIAID/NIH R21 grant number R21AI101685 and a MedImmune/University of Maryland joint research grant titled ?Immunotherapeutic potential of rationally designed Toll like receptor 4 (TLR4) mimetics using Pseudomonas and RSV antigens.?en_US
dc.description.urihttps://www.doi.org/10.1128/mBio.00492-17en_US
dc.language.isoen_USen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.relation.ispartofmBio
dc.subjectAdjuvantsen_US
dc.subjectImmunomodulationen_US
dc.subjectInnate immunityen_US
dc.subjectLipid Aen_US
dc.subjectLipopolysaccharideen_US
dc.subjectMemeticen_US
dc.subjectTLR4en_US
dc.subjectToll-like receptorsen_US
dc.titleRationally designed TLR4 ligands for vaccine adjuvant discoveryen_US
dc.typeArticleen_US
dc.identifier.doi10.1128/mBio.00492-17
dc.identifier.pmid28487429


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