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.
Highlights
Innate immunity plays a fundamental role in the defense against microorganisms
Since LPS core structures are often conserved in phylogenetically related organisms, we scanned the genomes of aProteobacteria looking for orthologues of glycosyltransferases not involved in O-PS synthesis
We have identified a B. abortus LPS gene whose disruption does not result in the loss of the O-PS but in an altered core, which is in contrast to all Brucella LPS genes described [10,22,23,24]
Summary
In addition to the passive action of physical and physicochemical barriers, the effectiveness of innate immunity relies on pathogen recognition receptors that quickly perceive the presence of invaders. Cells like macrophages and dendritic cells are equipped with a variety of pathogen recognition receptors, which can be activated by bacterial PAMP such as lipoproteins, glycolipids, peptidoglycan or DNA. A relevant model of this kind of pathogens is represented by the genus Brucella [1], a group of aProteobacteria that have a great impact on animal and human health worldwide, and whose virulence relies in part upon the failure of pathogen recognition receptors to sense Brucella during the initial stages of infection [2,3]
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