Mini ReviewAdaptation of Staphylococcus aureus to the cystic fibrosis lung
Introduction
Patients with cystic fibrosis (CF) are highly susceptible to S. aureus lung infections. In these patients, the pathogen evokes an intense host immune response in the lungs which is characterised above all by polymorphonuclear leukocytes (Saba et al., 2002). S. aureus multiplies and persists in the airways of CF patients for months or even years despite appropriate anti-staphylococcal therapy (Branger et al., 1996, Kahl et al., 1998, Kahl et al., 2003c). During chronic infection, pathogens will experience changing selection pressures as they encounter new habitats and different coinfecting species and as they respond to medical intervention. In the short term, regulatory mechanisms allow the pathogen to quickly change its phenotype in response to the microenvironment. In the long term, mutation or recombination together with purging selection enforced by the changing environment leads to inheritable shifts in the bacterial population. Adaptive strategies of S. aureus are illustrated by the formation of biofilms, the switch to small-colony variants, the occurrence of hypermutable strains, the downregulation of virulence genes, and the manifestation of a heterogeneous bacterial population. In the present review, we will discuss these different mechanisms of S. aureus to adapt to the highly selective environment of the CF lung. Some of these strategies lead to a resistant phenotype of S. aureus, making appropriate antibiotic therapy a challenge. Additionally, classical antibiotic-resistant bacteria (e.g. methicillin-resistant S. aureus) may be selected due to the high antibiotics consumption in these patients. That, however, is not the subject of the present review.
Section snippets
Small-colony variants of S. aureus in the cystic fibrosis lung
In numerous chronic infections, small-colony variants (SCVs) of S. aureus and other pathogens are regularly observed and are thought to reflect long-term adaptation of the organisms to the host environment (Proctor et al., 2006). SCVs of S. aureus are characterised by a slower growth rate, reduced expression of haemolysins and loss of pigmentation, but increased resistance towards aminoglycosides and a high capacity to persist after non-professional phagocytosis. Due to mutations in metabolic
Biofilm formation in the cystic fibrosis lung
Bacteria often grow in organized communities of aggregated cells embedded in a hydrated matrix of extracellular polymeric substances called biofilms (Costerton et al., 1999, Hall-Stoodley et al., 2004, Hall-Stoodley and Stoodley, 2009, Parsek and Singh, 2003). Device-related infections as well as CF lung infections are thought to be typically caused by biofilm-forming bacteria, which are protected in this way from the immune system and antibiotics. However, one major problem with these
Regulation and expression of virulence genes in the cystic fibrosis lung
In S. aureus, the expression of secreted virulence determinants, cell wall adhesins and extracellular polysaccharides is tightly linked to the growth cycle in vitro and is influenced by different environmental signals (Arvidson and Tegmark, 2001, Cheung et al., 2004, Goerke and Wolz, 2004b, Novick, 2003, Novick and Geisinger, 2008, Pragman and Schlievert, 2004). Differential gene expression is achieved by global regulatory loci such as agr, sar, sigB, and saeR/S. All of these regulators are
Intracellular replication and persistence in the cystic fibrosis lung?
Although there is no direct evidence for intracellular survival of S. aureus during CF lung infection, there are some indications that S. aureus may invade and replicate within the epithelium. In vitro it could be shown repeatedly that SCVs can persist within epithelial cells over a prolonged period of time (Proctor et al., 2006). Also the normal S. aureus phenotype can invade and replicate within a CF epithelial cell line (CFT-1) (Kahl et al., 2000, Jarry and Cheung, 2006). A fundamental
Bacterial interference in the cystic fibrosis lung
Antagonism within a microbial community is unavoidable due to competition for finite resources. This may involve simple resource competition or direct antagonistic effects on the growth or viability of competitors. There is evidence of antagonism between P. aeruginosa and S. aureus, the 2 species most frequently isolated from the CF lung. We could show that an inverse relationship existed between heterogeneity of the S. aureus population in the sputum samples and the simultaneous occurrence of
Hypermutable S. aureus isolates in the cystic fibrosis lung
Mutation plays a central role in the evolution of bacterial resistance to antibiotics. Hypermutable strains which display higher mutation frequencies than their normal counterparts contribute significantly to the adaptation of bacterial populations to stressful environments. For the most part, the hypermutator phenotype is caused by a defect in the methyl-directed mismatch repair system due to inactivation of mutS or mutL genes. The occurrence of hypermutators amongst S. aureus strains from CF
Genomic alterations in S. aureus in the cystic fibrosis lung
In addition to mutations, the occurrence of large genomic rearrangements can also enhance the genome plasticity of S. aureus during chronic CF lung infection. The frequency of genome alterations was significantly higher in S. aureus derived from CF patients (mean time: 1.03 years) than in isolates from healthy individuals (mean time: 13.4 years). In many cases, rearrangements could be linked to phage mobilization, especially to phage insertion or deletion in the β-hemolysin (Hlb) gene (Goerke
Heterogeneity of the S. aureus population in the cystic fibrosis lung
An ecological model termed the ‘insurance hypothesis’ predicts that a more diverse community will be better able to resist an external stress. Boles et al. (2004) applied this theory to the survival of bacterial pathogens during long-term infection. Niche separation within the host may favour the survival of bacterial subpopulations under selective pressure such as exposure to antibiotics or the human defence system. In accordance with the insurance hypothesis, the variation within a bacterial
Conclusions
S. aureus is a versatile pathogen which can adapt successfully to the highly stressful environment of the CF lung. The mechanism discussed here closely resembles similar mechanisms discovered for the leading CF pathogen P. aeruginosa: growth in multicellular aggregates encased in a polysaccharide matrix, development of SCVs, occurrence of hypermutators, and repression of typical virulence factors. Another common scheme is the establishment of a highly heterogeneous bacterial population,
Acknowledgement
This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Wo 578/6).
References (68)
- et al.
Regulation of virulence determinants in Staphylococcus aureus
Int. J. Med. Microbiol.
(2001) - et al.
Molecular analysis of the thymidine-auxotrophic small colony variant phenotype of Staphylococcus aureus
Int. J. Med. Microbiol.
(2007) - et al.
Purification and peptidase activity of a bacteriolytic extracellular enzyme from Pseudomonas aeruginosa
Res. Microbiol.
(1989) - et al.
Regulation of virulence determinants in vitro and in vivo in Staphylococcus aureus
FEMS Immunol. Med. Microbiol.
(2004) - et al.
Regulatory and genomic plasticity of Staphylococcus aureus during persistent colonization and infection
Int. J. Med. Microbiol.
(2004) - et al.
Staphylococcus quorum sensing in biofilm formation and infection
Int. J. Med. Microbiol.
(2006) - et al.
Vaccine potential of poly-1-6-beta-d-N-succinylglucosamine, an immunoprotective surface polysaccharide of Staphylococcus aureus and Staphylococcus epidermidis
J. Biotechnol.
(2000) - et al.
Protection from Staphylococcus aureus mastitis associated with poly-N-acetyl beta-1,6 glucosamine specific antibody production using biofilm-embedded bacteria
Vaccine
(2009) - et al.
Virulence regulation in Staphylococcus aureus: the need for in vivo analysis of virulence factor regulation
FEMS Immunol. Med. Microbiol.
(2004) - et al.
Prevalence and clinical significance of Staphylococcus aureus small-colony variants in cystic fibrosis lung disease
J. Clin. Microbiol.
(2007)
The thymidine-dependent small-colony-variant phenotype is associated with hypermutability and antibiotic resistance in clinical Staphylococcus aureus isolates
Antimicrob. Agents Chemother.
Staphylococcus aureus survival strategy to resist Pseudomonas aeruginosa is SCV selection
Appl. Environ. Microbiol.
Agr-mediated dispersal of Staphylococcus aureus biofilms
PLoS Pathog.
Self-generated diversity produces “insurance effects” in biofilm communities
Proc. Natl. Acad. Sci. USA
Persistence of Staphylococcus aureus strains among cystic fibrosis patients over extended periods of time
J. Med. Microbiol.
In vivo mutations of thymidylate synthase (encoded by thyA) are responsible for thymidine dependency in clinical small-colony variants of Staphylococcus aureus
J. Bacteriol.
The role of Staphylococcus aureus surface protein SasG in adherence and biofilm formation
Microbiology
Bacterial biofilms: a common cause of persistent infections
Science
Role of biofilm-associated protein bap in the pathogenesis of bovine Staphylococcus aureus
Infect. Immun.
Biofilm formation, icaADBC transcription, and polysaccharide intercellular adhesin synthesis by staphylococci in a device-related infection model
Infect. Immun.
Quantification of bacterial transcripts during infection using competitive reverse transcription-PCR (RT-PCR) and LightCycler RT-PCR
Clin. Diagn. Lab. Immunol.
Direct quantitative transcript analysis of the agr regulon of Staphylococcus aureus during human infection in comparison to the expression profile in vitro
Infect. Immun.
High phenotypic diversity in infecting but not in colonizing Staphylococcus aureus populations
Environ Microbiol.
Ciprofloxacin and trimethoprim cause phage induction and virulence modulation in Staphylococcus aureus
Antimicrob. Agents Chemother.
Evaluation of intraspecies interference due to agr polymorphism in Staphylococcus aureus during infection and colonization
J. Infect. Dis.
Increased frequency of genomic alterations in Staphylococcus aureus during chronic infection is in part due to phage mobilization
J. Infect. Dis.
Extensive phage dynamics in Staphylococcus aureus contributes to adaptation to the human host during infection
Mol. Microbiol.
Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1
Nat. Med.
Staphylococcus and biofilms
Mol. Microbiol.
Bacterial biofilms: from the natural environment to infectious diseases
Nat. Rev. Microbiol.
Evolving concepts in biofilm infections
Cell. Microbiol.
Regulation of Staphylococcus aureus capsular polysaccharide type 5: CO2 inhibition in vitro and in vivo
J. Infect. Dis.
Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa
Proc. Natl. Acad. Sci. USA
Exfoliatin-producing strains define a fourth agr specificity group in Staphylococcus aureus
J. Bacteriol.
Cited by (96)
Phylogenomics of nontuberculous mycobacteria respiratory infections in people with cystic fibrosis
2023, Paediatric Respiratory ReviewsThymidine starvation promotes c-di-AMP-dependent inflammation during pathogenic bacterial infection
2022, Cell Host and MicrobeCitation Excerpt :In many organisms, including Staphylococcus aureus, antibiotic therapy can drive the emergence of isolates harboring disruptions in genes involved in fundamental metabolic pathways. The resulting small colony variants (SCVs) exhibit slow in vitro growth and are associated with antibiotic-refractory, chronic infections, including osteomyelitis, endocarditis, wound infections, and lung infections in patients with the autosomal recessive disease cystic fibrosis (CF) (Goerke and Wolz, 2010; Proctor et al., 2006). As such, SCV infections are difficult to eradicate and can persist for many years.
Multimorbidity of Psoriasis: A Large-Scale Population Study of Its Associated Comorbidities
2024, Journal of Clinical MedicineA systematic review of the clinical impact of small colony variants in patients with cystic fibrosis
2023, BMC Pulmonary Medicine