title: The lipopolysaccharide core of Brucella abortus acts as a shield against innate immunity recognition.
abstract: Innate immunity recognizes bacterial molecules bearing pathogen-associated molecular patterns to launch inflammatory responses leading to the activation of adaptive immunity. However, the lipopolysaccharide (LPS) of the gram-negative bacterium Brucella lacks a marked pathogen-associated molecular pattern, and it has been postulated that this delays the development of immunity, creating a gap that is critical for the bacterium to reach the intracellular replicative niche. We found that a B. abortus mutant in the wadC gene displayed a disrupted LPS core while keeping both the LPS O-polysaccharide and lipid A. In mice, the wadC mutant induced proinflammatory responses and was attenuated. In addition, it was sensitive to killing by non-immune serum and bactericidal peptides and did not multiply in dendritic cells being targeted to lysosomal compartments. In contrast to wild type B. abortus, the wadC mutant induced dendritic cell maturation and secretion of pro-inflammatory cytokines. All these properties were reproduced by the wadC mutant purified LPS in a TLR4-dependent manner. Moreover, the core-mutated LPS displayed an increased binding to MD-2, the TLR4 co-receptor leading to subsequent increase in intracellular signaling. Here we show that Brucella escapes recognition in early stages of infection by expressing a shield against recognition by innate immunity in its LPS core and identify a novel virulence mechanism in intracellular pathogenic gram-negative bacteria. These results also encourage for an improvement in the generation of novel bacterial 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: Maite
authors.initials: M
authors.lastname: Iriarte
authors.forename: Mateja
authors.initials: M
authors.lastname: Manček-Keber
authors.forename: Elías
authors.initials: E
authors.lastname: Barquero-Calvo
authors.forename: Leyre
authors.initials: L
authors.lastname: Palacios-Chaves
authors.forename: Carlos
authors.initials: C
authors.lastname: Chacón-Díaz
authors.forename: Esteban
authors.initials: E
authors.lastname: Chaves-Olarte
authors.forename: Anna
authors.initials: A
authors.lastname: Martirosyan
authors.forename: Kristine
authors.initials: K
authors.lastname: von Bargen
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Grilló
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
authors.forename: Enrique
authors.initials: E
authors.lastname: Llobet
authors.forename: José A
authors.initials: JA
authors.lastname: Bengoechea
authors.forename: Edgardo
authors.initials: E
authors.lastname: Moreno
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moriyón
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gorvel
mesh_terms: D000818:Animals; D058947:Bacterial Secretion Systems; D002003:Brucella abortus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D002006:Brucellosis / Q000382:microbiology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D005260:Female; D057131:Immune Evasion; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D008050:Lipid A / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D058947:Bacterial Secretion Systems; D008050:Lipid A; D008070:Lipopolysaccharides; D008565:Membrane Proteins