title: Persistent Staphylococcus aureus isolates from two independent cases of bacteremia display increased bacterial fitness and novel immune evasion phenotypes.
abstract: Staphylococcus aureus bacteremia cases are complicated by bacterial persistence and treatment failure despite the confirmed in vitro susceptibility of the infecting strain to administered antibiotics. A high incidence of methicillin-resistant S. aureus (MRSA) bacteremia cases are classified as persistent and are associated with poorer patient outcomes. It is still unclear how S. aureus evades the host immune system and resists antibiotic treatment for the prolonged duration of a persistent infection. In this study, the genetic changes and associated phenotypic traits specific to S. aureus persistent bacteremia were identified by comparing temporally dispersed isolates from persistent infections (persistent isolates) originating from two independent persistent S. aureus bacteremia cases with the initial infection isolates and with three resolved S. aureus bacteremia isolates from the same genetic background. Several novel traits were associated specifically with both independent sets of persistent S. aureus isolates compared to both the initial isolates and the isolates from resolved infections (resolved isolates). These traits included (i) increased growth under nutrient-poor conditions; (ii) increased tolerance of iron toxicity; (iii) higher expression of cell surface proteins involved in immune evasion and stress responses; and (iv) attenuated virulence in a Galleria mellonella larva infection model that was not associated with small-colony variation or metabolic dormancy such as had been seen previously. Whole-genome sequence analysis identified different single nucleotide mutations within the mprF genes of all the isolates with the adaptive persistence traits from both independent cases. Overall, our data indicate a novel role for MprF function during development of S. aureus persistence by increasing bacterial fitness and immune evasion.
authors.affiliation: Department of Genetics and Infection, Immunity of Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: R L
authors.initials: RL
authors.lastname: Richards
authors.affiliation: Department of Genetics and Infection, Immunity of Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: R D
authors.initials: RD
authors.lastname: Haigh
authors.affiliation: Institute of Life Science, Swansea University College of Medicine, Swansea, United Kingdom.
authors.forename: B
authors.initials: B
authors.lastname: Pascoe
authors.affiliation: Institute of Life Science, Swansea University College of Medicine, Swansea, United Kingdom Department of Zoology, University of Oxford, Oxford, United Kingdom.
authors.forename: S K
authors.initials: SK
authors.lastname: Sheppard
authors.affiliation: Department of Clinical Microbiology, University Hospitals of Leicester, Leicester, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: Price
authors.affiliation: Department of Clinical Microbiology, University Hospitals of Leicester, Leicester, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Jenkins
authors.affiliation: Department of Genetics and Infection, Immunity of Inflammation, University of Leicester, Leicester, United Kingdom Department of Clinical Microbiology, University Hospitals of Leicester, Leicester, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Rajakumar
authors.affiliation: Department of Genetics and Infection, Immunity of Inflammation, University of Leicester, Leicester, United Kingdom jam26@le.ac.uk.
authors.forename: J A
authors.initials: JA
authors.lastname: Morrissey
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D016470:Bacteremia / Q000276:immunology / Q000382:microbiology*; D006801:Humans; D057131:Immune Evasion; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents