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Title: Host-pathogen interactions in chronic infections
Author: Arnold, Markus F. F.
ISNI:       0000 0004 2737 5611
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2012
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The BacA protein plays a key role in the symbiosis of Sinorhizobium meliloti with the leguminous plant alfalfa (Medicago sativa) and is proposed to be the transmembrane subunit of an ATP‐binding cassette (ABC) transporter. BacA homologues are also present in Brucella species, enteric bacteria (known as SbmA) and Mycobacterium tuberculosis. The S. meliloti‐alfalfa symbiosis, although beneficial to both partners, can also be viewed as a chronic infection. The M. tuberculosis BacA protein is important for M. tuberculosis for the maintenance of a chronic infection. In order to study the M. tuberculosis BacA protein a codon optimised M. tuberculosis bacA gene was synthesised and cloned into vectors for expression in an S. meliloti ΔbacA mutant. Evidence is presented that M. tuberculosis BacA sensitises an S. meliloti ΔbacA mutant towards the glycopeptide bleomycin and the truncated proline rich peptide Bac71‐16, and further that a functional ATPase domain is essential to perform BacA mediated peptide transport. The M. tuberculosis BacA protein protected an S. meliloti ΔbacA mutant from being killed by host defensins. In addition, it was determined that M. tuberculosis BacA‐mediated protection of the legume symbiont S. meliloti against legume defensins as well as mouse alveolar lavages and human ‐defensin 2 is dependent on an ATPase domain which is present in the M. tuberculosis BacA protein. M. tuberculosis encounters ‐defensins during mammalian infections in the host’s lungs and my data show that BacA is likely to be important in conferring immunity to these peptides. The mechanism of persistent infection by M. tuberculosis is therefore very reminiscent of the Sinorhizobium ‐ legume interaction. Also Salmonella enterica is able to cause asymptomatic infections and about 5% of these develop a chronic carrier state and are able to spread the pathogen. In enteric bacterial species SbmA is in close proximity to the putative lipoprotein YaiW. In this study it was determined that YaiW is exposed on the cell surface and that it is involved in the protection of E. coli and potentially Salmonella spp. against a cysteine rich host peptide. YaiW is potentially involved in swarming motility. It was also determined that an alfalfa plant infection model can distinguish between Salmonella strains forming acute and chronic infections. Staphylococcus aureus is one of the major hospital acquired and opportunistic pathogens. Asymptomatic carriers, infected with multi‐drug resistant strains (MRSA) pose a threat to immunocompromised individuals. Here, novel compounds and ways from a variety of sources have been tested for their potential antimicrobial activity against a range of multi‐drug resistant clinical S. aureus isolates. This project significantly advanced the molecular understanding of asymptomatic bacteria‐host infections and helped to understand and establish novel ways to treat infections with multi‐drug resistant clinical pathogens.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Host-parasite relationships ; Infection