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Background  During 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 Findings  In 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/Significance  The 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 .

The Differential Interaction of Brucella and Ochrobactrum with Innate Immunity Reveals Traits Related to the Evolution of Stealthy Pathogens