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Brucella ? 1,2 cyclic glucan is an activator of human and mouse dendritic cells.

ABSTRACT: Bacterial cyclic glucans are glucose polymers that concentrate within the periplasm of alpha-proteobacteria. These molecules are necessary to maintain the homeostasis of the cell envelope by contributing to the osmolarity of Gram negative bacteria. Here, we demonstrate that Brucella ? 1,2 cyclic glucans are potent activators of human and mouse dendritic cells. Dendritic cells activation by Brucella ? 1,2 cyclic glucans requires TLR4, MyD88 and TRIF, but not CD14. The Brucella cyclic glucans showed neither toxicity nor immunogenicity compared to LPS and triggered antigen-specific CD8(+) T cell responses in vivo. These cyclic glucans also enhanced antigen-specific CD4(+) and CD8(+) T cell responses including cross-presentation by different human DC subsets. Brucella ? 1,2 cyclic glucans increased the memory CD4(+) T cell responses of blood mononuclear cells exposed to recombinant fusion proteins composed of anti-CD40 antibody and antigens from both hepatitis C virus and Mycobacterium tuberculosis. Thus cyclic glucans represent a new class of adjuvants, which might contribute to the development of effective antimicrobial therapies.

SUBMITTER: Martirosyan A

PROVIDER: S-EPMC3499565 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Brucella β 1,2 cyclic glucan is an activator of human and mouse dendritic cells.

Martirosyan Anna A Pérez-Gutierrez Camino C Banchereau Romain R Dutartre Hélène H Lecine Patrick P Dullaers Melissa M Mello Marielle M Salcedo Suzana Pinto SP Muller Alexandre A Leserman Lee L Levy Yves Y Zurawski Gerard G Zurawski Sandy S Moreno Edgardo E Moriyón Ignacio I Klechevsky Eynav E Banchereau Jacques J Oh Sangkon S Gorvel Jean-Pierre JP

PLoS pathogens 20121115 11

Bacterial cyclic glucans are glucose polymers that concentrate within the periplasm of alpha-proteobacteria. These molecules are necessary to maintain the homeostasis of the cell envelope by contributing to the osmolarity of Gram negative bacteria. Here, we demonstrate that Brucella β 1,2 cyclic glucans are potent activators of human and mouse dendritic cells. Dendritic cells activation by Brucella β 1,2 cyclic glucans requires TLR4, MyD88 and TRIF, but not CD14. The Brucella cyclic glucans show ...[more]

PMID: 23166489

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Project description:UnlabelledCyclic ?-1,2-glucans (C?G) are periplasmic homopolysaccharides that play an important role in the virulence and interaction of Brucella with the host. Once synthesized in the cytoplasm by the C?G synthase (Cgs), C?G are transported to the periplasm by the C?G transporter (Cgt) and succinylated by the C?G modifier enzyme (Cgm). Here, we used a bacterial two-hybrid system and coimmunoprecipitation techniques to study the interaction network between these three integral inner membrane proteins. Our results indicate that Cgs, Cgt, and Cgm can form both homotypic and heterotypic interactions. Analyses carried out with Cgs mutants revealed that the N-terminal region of the protein (Cgs region 1 to 418) is required to sustain the interactions with Cgt and Cgm as well as with itself. We demonstrated by single-cell fluorescence analysis that in Brucella, Cgs and Cgt are focally distributed in the membrane, particularly at the cell poles, whereas Cgm is mostly distributed throughout the membrane with a slight accumulation at the poles colocalizing with the other partners. In summary, our results demonstrate that Cgs, Cgt, and Cgm form a membrane-associated biosynthetic complex. We propose that the formation of a membrane complex could serve as a mechanism to ensure the fidelity of C?G biosynthesis by coordinating their synthesis with the transport and modification.ImportanceIn this study, we analyzed the interaction and localization of the proteins involved in the synthesis, transport, and modification of Brucella abortus cyclic ?-1,2-glucans (C?G), which play an important role in the virulence and interaction of Brucella with the host. We demonstrate that these proteins interact, forming a complex located mainly at the cell poles; this is the first experimental evidence of the existence of a multienzymatic complex involved in the metabolism of osmoregulated periplasmic glucans in bacteria and argues for another example of pole differentiation in Brucella. We propose that the formation of this membrane complex could serve as a mechanism to ensure the fidelity of C?G biosynthesis by coordinating synthesis with the transport and modification.

Dataset Information

Brucella ? 1,2 cyclic glucan is an activator of human and mouse dendritic cells.

Publications

Brucella β 1,2 cyclic glucan is an activator of human and mouse dendritic cells.

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