Abstract
BackgroundDuring evolution, innate immunity has been tuned to recognize pathogen-associated molecular patterns. However, some α-Proteobacteria are stealthy intracellular pathogens not readily detected by this system. Brucella members follow this strategy and are highly virulent, but other Brucellaceae like Ochrobactrum are rhizosphere inhabitants and only opportunistic pathogens. To gain insight into the emergence of the stealthy strategy, we compared these two phylogenetically close but biologically divergent bacteria.Methodology/Principal FindingsIn contrast to Brucella abortus, Ochrobactrum anthropi did not replicate within professional and non-professional phagocytes and, whereas neutrophils had a limited action on B. abortus, they were essential to control O. anthropi infections. O. anthropi triggered proinflammatory responses markedly lower than Salmonella enterica but higher than B. abortus. In macrophages and dendritic cells, the corresponding lipopolysaccharides reproduced these grades of activation, and binding of O. anthropi lipopolysaccharide to the TLR4 co-receptor MD-2 and NF-κB induction laid between those of B. abortus and enteric bacteria lipopolysaccharides. These differences correlate with reported variations in lipopolysaccharide core sugars, sensitivity to bactericidal peptides and outer membrane permeability.Conclusions/SignificanceThe results suggest that Brucellaceae ancestors carried molecules not readily recognized by innate immunity, so that non-drastic variations led to the emergence of stealthy intracellular parasites. They also suggest that some critical envelope properties, like selective permeability, are profoundly altered upon modification of pathogen-associated molecular patterns, and that this represents a further adaptation to the host. It is proposed that this adaptive trend is relevant in other intracellular α-Proteobacteria like Bartonella, Rickettsia, Anaplasma, Ehrlichia and Wolbachia.
Highlights
The class a-Proteobacteria includes microorganisms capable of establishing close associations with eukaryotic cells in a wide range of lifestyles
Proinflammatory cytokines, TNF-a, increase during acute Gram negative infections but not at the onset of brucellosis. When we studied this in comparative terms, we found that murine macrophages infected with O. anthropi released significantly higher amounts of TNF-a than cells infected with B. abortus (Fig. 6A), and this observation held true in vivo since mice displayed higher TNF-a blood levels when inoculated with O. anthropi than with B. abortus (Fig. 6B)
We proposed that B. abortus follows a stealthy strategy which relies on the absence, modification and inaccessibility of pathogen-associated molecular pattern (PAMP)
Summary
The class a-Proteobacteria includes microorganisms capable of establishing close associations with eukaryotic cells in a wide range of lifestyles. Some bacteria close to Brucella are free living environmental microorganisms like Ochrobactrum, Daeguia, Crabtreella and Mycoplana These four genera are included in the Brucellaceae (http://www.bacterio.cict.fr/), only Ochrobactrum has been reported to display some degree of pathogenicity. Ochrobactrum anthropi, primarily a rhizosphere inhabitant, has been isolated from immunocompromised individuals or patients subjected to dialysis, catheterization, surgical interventions or transplantation [4,5,6,7,8,9,10,11] and often shows a broad antibiotic resistance [12,13] Ochrobactrum intermedium is another opportunistic member of the genus. Some a-Proteobacteria are stealthy intracellular pathogens not readily detected by this system Brucella members follow this strategy and are highly virulent, but other Brucellaceae like Ochrobactrum are rhizosphere inhabitants and only opportunistic pathogens. To gain insight into the emergence of the stealthy strategy, we compared these two phylogenetically close but biologically divergent bacteria
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