Extended Staphylococcus aureus persistence in cystic fibrosis is associated with bacterial adaptation

Nina, Hirschhausen; Block, Desirée; Bianconi, Irene; Bragonzi, Alessandra; Birtel, Johannes; Lee, Jean C.; Dübbers, Angelika; Kühnl, P.; Janina, Kahl; Peters, Georg; Kahl, Barbara C.

doi:10.1016/j.ijmm.2013.09.012

Cited by 76 publications

(82 citation statements)

References 29 publications

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“…Later, Pseudomonas aeruginosa, which is the most prevalent pathogen in CF, replaces S. aureus and infects more than 80% of adult CF patients (72). Although CF patients are regularly treated with antibiotics directed against the respective pathogens, the same S. aureus clone persists in the airways for many years (73)(74)(75). Such persistence is even more pronounced for P. aeruginosa, which in many patients persists lifelong once chronic airway infection has been established (76).…”

Section: Cystic Fibrosis Airway Infectionmentioning

confidence: 99%

“…To study the impact of SCVs on the pathogenesis of lung infections in CF, it would be necessary to use a chronic lung infection model which mimics CF airway disease. Recently, a model was initiated which uses bacteria implemented into agar beads, which are placed directly via incision into the trachea (75). The authors of that study followed airway infection for 2 weeks.…”

Section: Animal Models For Studying the Formation And Persistence Of mentioning

confidence: 99%

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Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

2016

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SUMMARYSmall colony variants (SCVs) were first described more than 100 years ago forStaphylococcus aureusand various coagulase-negative staphylococci. Two decades ago, an association between chronic staphylococcal infections and the presence of SCVs was observed. Since then, many clinical studies and observations have been published which tie recurrent, persistent staphylococcal infections, including device-associated infections, bone and tissue infections, and airway infections of cystic fibrosis patients, to this special phenotype. By their intracellular lifestyle, SCVs exhibit so-called phenotypic (or functional) resistance beyond the classical resistance mechanisms, and they can often be retrieved from therapy-refractory courses of infection. In this review, the various clinical infections where SCVs can be expected and isolated, diagnostic procedures for optimized species confirmation, and the pathogenesis of SCVs, including defined underlying molecular mechanisms and the phenotype switch phenomenon, are presented. Moreover, relevant animal models and suggested treatment regimens, as well as the requirements for future research areas, are highlighted.

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Section: Cystic Fibrosis Airway Infectionmentioning

confidence: 99%

Section: Animal Models For Studying the Formation And Persistence Of mentioning

confidence: 99%

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

2016

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“…The presence of S. aureus is correlated with worse lung function and lower forced expiratory volume (FEV), poorer nutrition, and increased inflammation in children (21,22). Further, strains of S. aureus may persist in patients through adaptation of numerous virulence factors, including capsule, hemolysis, biofilm formation, and antibiotic resistance (particularly methicillin resistance) (23) and through the formation of small-colony variants (SCVs) (24). P. aeruginosa is detected in patients of all ages but is typically most prevalent and abundant in adult patients (20).…”

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confidence: 99%

Coculture of Staphylococcus aureus with Pseudomonas aeruginosa Drives S. aureus towards Fermentative Metabolism and Reduced Viability in a Cystic Fibrosis Model

et al. 2015

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The airways of patients with cystic fibrosis are colonized with diverse bacterial communities that change dynamically during pediatric years and early adulthood. Staphylococcus aureus is the most prevalent pathogen during early childhood, but during late teens and early adulthood, a shift in microbial composition occurs leading to Pseudomonas aeruginosa community predominance in ϳ50% of adults. We developed a robust dual-bacterial in vitro coculture system of P. aeruginosa and S. aureus on monolayers of human bronchial epithelial cells homozygous for the ⌬F508 cystic fibrosis transmembrane conductance regulator (CFTR) mutation to better model the mechanisms of this interaction. We show that P. aeruginosa drives the S. aureus expression profile from that of aerobic respiration to fermentation. This shift is dependent on the production of both 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) and siderophores by P. aeruginosa. Furthermore, S. aureus-produced lactate is a carbon source that P. aeruginosa preferentially consumes over medium-supplied glucose. We find that initially S. aureus and P. aeruginosa coexist; however, over extended coculture P. aeruginosa reduces S. aureus viability, also in an HQNO-and P. aeruginosa siderophore-dependent manner. Interestingly, S. aureus small-colony-variant (SCV) genetic mutant strains, which have defects in their electron transport chain, experience reduced killing by P. aeruginosa compared to their wild-type parent strains; thus, SCVs may provide a mechanism for persistence of S. aureus in the presence of P. aeruginosa. We propose that the mechanism of P. aeruginosa-mediated killing of S. aureus is multifactorial, requiring HQNO and P. aeruginosa siderophores as well as additional genetic, environmental, and nutritional factors. IMPORTANCEIn individuals with cystic fibrosis, Staphylococcus aureus is the primary respiratory pathogen during childhood. During adulthood, Pseudomonas aeruginosa predominates and correlates with worse patient outcome. The mechanism(s) by which P. aeruginosa outcompetes or kills S. aureus is not well understood. We describe an in vitro dual-bacterial species coculture system on cystic fibrosis-derived airway cells, which models interactions relevant to patients with cystic fibrosis. Further, we show that molecules produced by P. aeruginosa additively induce a transition of S. aureus metabolism from aerobic respiration to fermentation and eventually lead to loss of S. aureus viability. Elucidating the molecular mechanisms of P. aeruginosa community predominance can provide new therapeutic targets and approaches to impede this microbial community transition and subsequent patient worsening. C omplex polymicrobial communities colonize the airways of cystic fibrosis (CF) patients within the first month of life (1). Culture-independent studies have revealed the simultaneous presence of numerous bacterial taxa, fungi, and viruses in respiratory samples from CF patients at all stages of life (2-8). This abundance of microbes colonizing the respiratory ...

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“…During the course of infection, S. aureus frequently acquires mutations that affect the expression of virulence factors (55)(56)(57)(58)(59). However, the mechanisms by which these mutations influence the expression of specific virulence factors are not always clear.…”

Section: Discussionmentioning

confidence: 99%

The Agr Quorum-Sensing System Regulates Fibronectin Binding but Not Hemolysis in the Absence of a Functional Electron Transport Chain

et al. 2014

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Staphylococcus aureus is responsible for numerous chronic and recurrent infections, which are frequently associated with the emergence of small-colony variants (SCVs) that lack a functional electron transport chain. SCVs exhibit enhanced expression of fibronectin-binding protein (FnBP) and greatly reduced hemolysin production, although the basis for this is unclear. One hypothesis is that these phenotypes are a consequence of the reduced Agr activity of SCVs, while an alternative is that the lack of a functional electron transport chain and the resulting reduction in ATP production are responsible. Disruption of the electron transport chain of S. aureus genetically (hemB and menD) or chemically, using 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), inhibited both growth and Agr activity and conferred an SCV phenotype. Supplementation of the culture medium with synthetic autoinducing peptide (sAIP) significantly increased Agr expression in both hemB mutant strains and S. aureus grown with HQNO and significantly reduced staphylococcal adhesion to fibronectin. However, sAIP did not promote hemolysin expression in hemB mutant strains or S. aureus grown with HQNO. Therefore, while Agr regulates fibronectin binding in SCVs, it cannot promote hemolysin production in the absence of a functional electron transport chain.

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Extended Staphylococcus aureus persistence in cystic fibrosis is associated with bacterial adaptation

Cited by 76 publications

References 29 publications

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

Coculture of Staphylococcus aureus with Pseudomonas aeruginosa Drives S. aureus towards Fermentative Metabolism and Reduced Viability in a Cystic Fibrosis Model

The Agr Quorum-Sensing System Regulates Fibronectin Binding but Not Hemolysis in the Absence of a Functional Electron Transport Chain

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