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

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

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