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

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.

N -Formyl-Perosamine Surface Homopolysaccharides Hinder the Recognition of Brucella abortus by Mouse Neutrophils

“…In the absence of opsonization by specific antibodies or complement, PMNs may also ingest microorganisms through the pathways of other PMN pattern recognition receptor (PRRs), such as ␤2 integrins, C-type lectins, or scavenger or pentraxin receptors (22,35,36). This explains the failure of mouse PMN PRRs to recognize putative B. abortus pathogen-associated molecular patterns (PAMPs), such as outer membrane lipoproteins, adhesion-like proteins, ornithinecontaining lipids, flagellar structures, and phospholipids, among the most conspicuous elements on the surface of brucellae, which in other bacteria are constitutive PAMPs and targets for recognition (7,8,14,27,37).…”

“…Finally, the almost absolute resistance to the killing action of mouse complement and PMNs is linked to the absence of activation of these elements by the putative Brucella PAMPs (5,7,8,14,27,37), as well as to the bacterial resistance to the microbicidal substances of PMNs (33,34). Regarding this, decreased lytic activity of mouse complement in comparison to that of the human counterpart has been described (53).…”

“…Although in the natural host and in humans Brucella also invades PMNs (2)(3)(4), the bacterium fails to replicate in these cells and just resists their killing action without inducing significant activation (3)(4)(5)(6). Indeed, Brucellainfected PMNs do not degranulate and induce low levels of reactive oxygen species (ROS) and cytokines, and the infection follows its course without significant neutrophilia (5,7,8). Likewise, the PMNs infiltration of the cervical lymph nodes after oral infection is very low, even in well-developed granulomas after 15 days of infection (9).…”

Identification of Brucella abortus virulence proteins that modulate the host immune response

“…7 The low endotoxic B. abortus LPS dramatically reduces and delays inflammatory response in the infected hosts compared with the endotoxins from other Gram-negative bacteria. 8 In addition, due to the particular function and structure of Brucella LPS, which avoids the activation of the macrophage-killing systems and confers resistance to the pathogen against the microbicidal action of antibiotics, Brucella are able to survive and multiply inside phagocytic cells without provoking their capacity to establish a chronic infection. In the past 10 years, the study of Brucella pathogenicity has been focused mainly on identifying factors that affect the intracellular trafficking and multiplication of the bacterium within the host cell.…”

Fatal Case of Brucellosis Misdiagnosed in Early Stages of Brucella suis Infection in a 46-Year-Old Patient with Marfan Syndrome

“…Ochrobactrum anthropi, a wellstudied pathogenic species of this genus, is recognized as a saprophyte and is occasionally associated with endocarditis, bacteremia, and nosocomial infections (2,24). Because of their similar phenotypic properties, early diagnosis of a suspected brucellosis case is often miscoded as O. anthropi infection by rapid automated identification systems in the clinical laboratory (10).…”