Adaptation of Staphylococcus aureus to the cystic fibrosis lung

Abstract

Staphylococcus aureus colonizes the lungs of cystic fibrosis (CF) patients and despite treatment with antibiotics results in recurrent and relapsing infections. With increasing duration of the infection, the bacterial population is exposed more and more to changing selective pressures exerted by the host immune system, to frequent therapeutic interventions, and to interference with other microorganisms. S. aureus has evolved a variety of strategies to adapt to these challenges: Recombination and mutation provide the population with a preselected heterogeneity, resulting in an inheritable shift of phenotypic traits. This includes the emergence of isolates with mutations in metabolic (e.g. small-colony variants) and regulatory (e.g. agr mutants) genes. Additionally, phages become mobilized with a higher frequency during infection, raising the propensity for recombination. On the other hand, S. aureus can also adapt to the CF lung using regulatory mechanisms which are not well understood in this context. The quorum-sensing system agr is not activated during lung infection in CF, which is consistent with a proposed biofilm mode of growth in the lungs and also with the observation that in CF patients the organism usually remains localized in the lungs without systemic manifestation. Altogether, adaptive processes result in the generation of a heterogeneous S. aureus population in the CF lung which is highly protected against antibiotic therapy, expressing factors necessary for persistence rather than virulence.

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.