Abstract
ABSTRACTAggregatibacter actinomycetemcomitans and Aggregatibacter aphrophilus belong to the HACEK group of fastidious Gram-negative organisms, a recognized cause of infective endocarditis. A. actinomycetemcomitans is also implicated in aggressive forms of periodontitis. We demonstrated that A. aphrophilus strains, as A. actinomycetemcomitans are ubiquitously serum resistant. Both species encode two Outer membrane protein A paralogues, here denoted OmpA1 and OmpA2. As their respective pangenomes contain several OmpA1 and OmpA2 alleles, they represent potential genotypic markers. A naturally competent strain of A. actinomycetemcomitans and A. aphrophilus, respectively were used to elucidate if OmpA1 and OmpA2 contribute to serum resistance. Whereas OmpA1 was critical for survival of A. actinomycetemcomitans D7SS in 50% normal human serum (NHS), serum resistant ompA1 mutants were fortuitously obtained, expressing enhanced levels of OmpA2. Similarly, OmpA1 rather than OmpA2 was a major contributor to serum resistance of A. aphrophilus HK83. Far-Western blot revealed that OmpA1AA, OmpA2AA, and OmpA1AP can bind to C4-binding protein, an inhibitor of classical and mannose-binding lectin (MBL) complement activation. Indeed, ompA1 mutants were susceptible to these pathways, but also to alternative complement activation. This may at least partly reflect a compromised outer membrane integrity but is also consistent with alternative mechanisms involved in OmpA-mediated serum resistance.
Highlights
The HACEK group of fastidious Gram-negative organisms is a recognized cause of infective endocarditis, responsible for 1.4 to 3% of cases [1], with the genus Aggregatibacter being the dominant etiology of HACEK endocarditis [2]
The observation that most whole genomesequenced A. actinomycetemcomitans and A. aphrophilus strains encode two OmpA paralogues is in accordance with findings with a number of other Gram-negative species, e.g., Aeromonas salmonicida, Bacteroides fragilis, Haemophilus ducreyi, and Porphyromonas gingivalis [19,41,42,43]
The observation that A. aphrophilus strains, similar to A. actinomycetemcomitans are ubiquitously resistant to killing by normal human serum is consistent with their association with extra-oral infections such as infective endocarditis and cerebral abscesses [2]
Summary
The HACEK group of fastidious Gram-negative organisms is a recognized cause of infective endocarditis, responsible for 1.4 to 3% of cases [1], with the genus Aggregatibacter being the dominant etiology of HACEK endocarditis [2]. Colonization by the human oral bacterium, Aggregatibacter actinomycetemcomitans is strongly associated with aggressive forms of periodontitis in adolescents and young adults [3,4]. The systemic role of A. actinomycetemcomitans, in addition to its involvement in endocarditis, includes its association with cases of soft tissue abscesses, and osteomyelitis [8], and the species can be detected in atheromatous plaque [9]. It is not known if there are specific genotypes of A. actinomycetemcomitans (or A. aphrophilus) that are more prone to translocate to the peripheral circulation
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