Genetic and functional basis of Acinetobacter baumannii virulence

Abstract

Acinetobacter baumannii is an opportunistic nosocomial pathogen and many strains are multior pan-drug resistant. Although this bacterium has long been regarded as a low-grade pathogen, it can cause a broad range of severe infections, including pneumonia and bacteraemia, but also secondary meningitis, skin and soft-tissue, wound and urinary tract infections, and attributable mortality rates can reach 35%. However, the virulence traits and pathogenic potential of A. baumannii remain elusive. The aim of this PhD thesis was to study the factors and mechanisms responsible for A. baumannii pathogenicity. The following main questions were asked: 1) is there a core set of conserved A. baumannii virulence factors? 2) did epidemic strains acquire new virulence determinants? 3) did a co-evolution between drug resistance and virulence occur? 4) is it possible to differentiate strains on the basis of their virulence factor profile? 5) is it possible to gain advantage from basic knowledge of A. baumannii metabolism to develop alternative therapeutic strategies against multidrug-resistant A. baumannii? To address these questions, the genomes of epidemiologically diverse A. baumannii strains were compared, and genomic information was used as a guidance tool for phenotypic analyses (Chapters 2 and 3). As the second step, the distribution of a particular group of virulence determinants, i.e. iron uptake systems, was explored in more depth using a wide, representative collection of clinical, MDR A. baumannii strains (Chapters 4 and 5). Thirdly, the expression of putative A. baumannii virulence-associated traits identified in Chapters 2 and 3 was studied in a collection of epidemic strains (Chapter 6). Lastly, a new antimicrobial strategy based on the disruption of iron metabolism was investigated (Chapter 7). It was shown that A. baumannii has the potential to express a wide repertoire of putative virulence factors that are common to the genomes of most strains, but that these factors can be differentially expressed according to the strain. Additionally, it was found that epidemic strains had not acquired any new specific virulence determinants in addition to antibiotic resistance genes. Thirdly, a multiplicity of iron uptake capabilities was identified, consistent with the importance of iron for A. baumannii metabolism. This evidence ultimately prompted the assessment of a novel anti-A. baumannii strategy based on the disruption of iron metabolism by gallium, an iron-mimetic metal. The results presented in this thesis revealed that A. baumannii is a very adaptable pathogen, possessing many diverse virulence attributes, and that it has an extraordinary ability to acquire new genetic material. Thus, although A. baumannii has long been considered a low-grade pathogen, in the future it could acquire new virulence genes in addition to antibiotic resistance genes, and become a more significant threat to human health. Hence, novel therapeutic strategies will continue to be needed to combat such a rapidly evolving pathogen, which already has an uncertain clinical outcome.