Vibrio Cholerae Proteome-Wide Screen for Immunostimulatory Proteins Identifies Phosphatidylserine Decarboxylase as a Novel Toll-Like Receptor 4 Agonist

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Vibrio Cholerae Proteome-Wide Screen for Immunostimulatory Proteins Identifies Phosphatidylserine Decarboxylase as a Novel Toll-Like Receptor 4 Agonist

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dc.contributor.author Montor, Wagner R.
dc.contributor.author LaBaer, Joshua
dc.contributor.author Thanawastien, Ann
dc.contributor.author Mekalanos, John J.
dc.contributor.author Yoon, Sanghyun James
dc.date.accessioned 2012-02-14T00:50:36Z
dc.date.issued 2009
dc.identifier.citation Thanawastien, Ann, Wagner R. Montor, Joshua LaBaer, John J. Mekalanos, and Sang Sun Yoon. 2009. Proteome-Wide Screen for Immunostimulatory Proteins Identifies Phosphatidylserine Decarboxylase as a Novel Toll-Like Receptor 4 Agonist. PLoS Pathogens 5, no. 8: e1000556. en_US
dc.identifier.issn 1553-7366 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8160861
dc.description.abstract Recognition of conserved bacterial components provides immediate and efficient immune responses and plays a critical role in triggering antigen-specific adaptive immunity. To date, most microbial components that are detected by host innate immune system are non-proteinaceous structural components. In order to identify novel bacterial immunostimulatory proteins, we developed a new high-throughput approach called “EPSIA”, Expressed Protein Screen for Immune Activators. Out of 3,882 Vibrio cholerae proteins, we identified phosphatidylserine decarboxylase (PSD) as a conserved bacterial protein capable of activating host innate immunity. PSD in concentrations as low as 100 ng/ml stimulated RAW264.7 murine macrophage cells and primary peritoneal macrophage cells to secrete TNFα and IL-6, respectively. PSD-induced proinflammatory response was dependent on the presence of MyD88, a known adaptor molecule for innate immune response. An enzymatically inactive PSD mutant and heat-inactivated PSD induced ∼40% and ∼15% of IL-6 production compared to that by native PSD, respectively. This suggests that PSD induces the production of IL-6, in part, via its enzymatic activity. Subsequent receptor screening determined TLR4 as a receptor mediating the PSD-induced proinflammatory response. Moreover, no detectable IL-6 was produced in TLR4-deficient mouse macrophages by PSD. PSD also exhibited a strong adjuvant activity against a co-administered antigen, BSA. Anti-BSA response was decreased in TLR4-deficient mice immunized with BSA in combination with PSD, further proving the role of TLR4 in PSD signaling in vivo. Taken together, these results provide evidence for the identification of V. cholerae PSD as a novel TLR4 agonist and further demonstrate the potential application of PSD as a vaccine adjuvant. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi://10.1371/journal.ppat.1000556 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722020/pdf/ en_US
dc.relation.hasversion www.plospathogens.org en_US
dash.license LAA
dc.subject microbiology en_US
dc.subject immunity to infections en_US
dc.subject innate immunity en_US
dc.subject medical microbiology en_US
dc.title Vibrio Cholerae Proteome-Wide Screen for Immunostimulatory Proteins Identifies Phosphatidylserine Decarboxylase as a Novel Toll-Like Receptor 4 Agonist en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Pathogens en_US
dash.depositing.author Yoon, Sanghyun James
dc.date.available 2012-02-14T00:50:36Z
dash.affiliation.other HMS^Microbiology and Molecular Genetics en_US
dash.affiliation.other HMS^Health Sciences and Technology en_US
dash.affiliation.other HMS^Microbiology and Molecular Genetics en_US

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