Host-adapted metabolism of Staphylococcus aureus Small-Colony Variants

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Staphylococcus aureus small-colony variants (SCVs) represent a phenotypic subpopulation specifically adapted for an intracellular life style and typically leading to the clinical course of chronic-persistent, often therapy-refractory infections. For the first time, the metabolism of a natural, clinically derived SCV was investigated showing that phenotype switch-related metabolic alterations are more complex than reflected by defined electron transport chain-interrupting SCV-mimicking mutants used hitherto. In comparison to parental strains with normal phenotype, we will investigate the pathogen´s metabolic and physiological adaption onto the intracellular lifestyle (i) by genome-wide determination of putative genetic alterations in the course of the SCV phenotype formation and (ii) by functional analysis of the impact of non-protein coding regulatory RNAs on the phenotype formation. In parallel to the characterization of the S. aureus internalization into host cells and intracellular persistence, the host cell response will be analyzed. Metabolic and physiological changes will be analyzed by proteomic and bioanalytical (isotopologue) approaches. In particular, in vivo models for initiation of an experimentally provoked bidirectional phenotype switch will be developed to (i) trace and characterize the phenotype switch-related metabolic changes and (ii) to document experimentally their consequences on the clinical course of an infection and, thus, opening up alternative ways to influence therapeutically acute and chronic S. aureus infections.