Molecular basis of bacterial small-colony variants / Base moléculaire des variants à petites colonies chez les bactéries

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Staphylococcus aureus (SA) and antibiotic resistant methicillin-resistant SA (MRSA) often cause chronic and difficult-to-treat infections. SA/MRSA are able to generate Small-Colony Variants (SCVs), which have been linked to persistent infections. The ability of SA/MRSA to switch to SCVs and vice versa seems to be an integral part the infection process leading to persistence. Compared to their normal counterparts, bacterial SCVs produce high amounts of protective biofilms (extracellular matrix in which bacteria are embedded). SCVs also have a great ability to survive and persist within host cells, a property that protects them from the host immune response. The switch to SCVs also facilitates the development of antibiotic resistance making SA/MRSA infections even more difficult to treat.*******This research program aims to study the molecular basis of SCV formation.*******The specific objectives are to: 1) Investigate the molecular basis of SCV formation through whole-genome sequencing (DNA and RNA) of genetically-related "SA-SCV" pairs; 2) Investigate the molecular basis of antibiotic resistance development occurring through SCVs; 3) Study the impact of SCV formation on virulence and persistence in the mammalian host; and 4) Establish the molecular basis of future strategies targeting SCVs.*******In Objectives 1 and 2, genome and transcriptome alterations responsible for the SCV phenotype will be identified. We expect finding different paths leading to SCV formation since several phenotypic expressions exist. We will then use a variety of in vitro, cellular and animal models to investigate how the different molecular mechanisms of SCV formation impact on virulence and persistence in the host (Objective 3). Objective 4 will built on these results to investigate and establish the molecular basis of new approaches to control SCVs such as the development of vaccines specifically tailored to target intracellular SA.*******Chronic lung infection is the most common cause of morbidity and mortality in cystic fibrosis (CF) patients. SA/MRSA is overall the most frequently isolated pathogen from CF patients and SCVs contribute to the persistence of infection. Studies have demonstrated the deleterious effects of SCVs and of MRSA on CF in children and adults, respectively. SCVs are also involved in the persistence of other diseases like bovine mastitis. Milk production is an important industry in Canada. Total losses linked to mastitis in dairy herds are estimated at over $400 million per year and SA is the leading cause of bovine mastitis in Canada. No SA vaccine has shown protective efficacy to date, in part because of the inadequacy of the immune response to counteract intracellular forms of SA. With the understanding of the fundamental mechanisms explaining the formation of SCVs, this research program will help the future development of specific antibiotics or vaccines that prevent SCV formation and SA/MRSA persistence.******