title: Lipopolysaccharide as a target for brucellosis vaccine design.
abstract: The gram-negative bacteria of the genus Brucella are facultative intracellular parasites that cause brucellosis, a world wide-distributed zoonotic disease that represents a serious problem for animal and human health. There is no human-to-human contagion and, since there is no human vaccine, animal vaccination is essential to control brucellosis. However, current vaccines (all developed empirically) do not provide 100% protection and are infectious in humans. Attempts to generate new vaccines by obtaining mutants lacking the lipopolysaccharide O-polysaccharide, in purine metabolism or in Brucella type IV secretion system have not been successful. Here we propose a new approach to develop brucellosis vaccines based on the concept that Brucella surface molecules evade efficient detection by innate immunity, thus delaying protective Th1 responses and opening a time window to reach sheltered intracellular compartments. We showed recently that a branch of the core oligosaccharide section of Brucella lipopolysaccharide hampers recognition by TLR4-MD2. Mutation of glycosyltransferase WadC, involved in the synthesis of this branch, results in a lipopolysaccharide that, while keeping the O-polysaccharide essential for optimal protection, shows a truncated core, is more efficiently recognized by MD2 and triggers an increased cytokine response. In keeping with this, the wadC mutant is attenuated in dendritic cells and mice. In the mouse model of brucellosis vaccines, the Brucella abortus wadC mutant conferred protection similar to that provided by S19, the best cattle vaccine available. The properties of the wadC mutant provide the proof of concept for this new approach and open the way for more effective brucellosis vaccines.
authors.affiliation: Institute for Tropical Health and Departamento de Microbiología y Parasitología, Universidad de Navarra, Pamplona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Conde-Álvarez
authors.forename: Vilma
authors.initials: V
authors.lastname: Arce-Gorvel
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gil-Ramírez
authors.forename: Maite
authors.initials: M
authors.lastname: Iriarte
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Grilló
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Gorvel
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moriyón
mesh_terms: D000818:Animals; D058491:Bacterial Load; D002004:Brucella Vaccine / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002003:Brucella abortus / Q000201:enzymology / Q000235:genetics; D002006:Brucellosis / Q000276:immunology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000639:trends; D055786:Gene Knockout Techniques; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019081:O Antigens / Q000096:biosynthesis / Q000276:immunology*; D013154:Spleen / Q000382:microbiology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D002004:Brucella Vaccine; D008070:Lipopolysaccharides; D019081:O Antigens; D014613:Vaccines, Attenuated; D016695:Glycosyltransferases