Understanding Staphylococcus aureus internalisation and induction of antimicrobial tolerance

ABSTRACT

Introduction

Staphylococcus aureus, a human commensal, is also one of the most common and serious pathogens for humans. In recent years, its capacity to survive and replicate in phagocytic and non-phagocytic cells has been largely demonstrated. In these intracellular niches, bacteria are shielded from the immune response and antibiotics, turning host cells into long-term infectious reservoirs. Moreover, neutrophils carry intracellular bacteria in the bloodstream, leading to systemic spreading of the disease. Despite the serious threat posed by intracellular S. aureus to human health, the molecular mechanisms behind its intracellular survival and subsequent antibiotic treatment failure remain elusive.

Area covered

We give an overview of the killing mechanisms of phagocytes and of the impressive arsenal of virulence factors, toxins and stress responses deployed by S. aureus as a response. We then discuss the different barriers to antibiotic activity in this intracellular niche and finally describe innovative strategies to target intracellular persisting reservoirs.

Expert opinion

Intracellular niches represent a challenge in terms of diagnostic and treatment. Further research using ad-hoc in-vivo models and single cell approaches are needed to better understand the molecular mechanisms underlying intracellular survival and tolerance to antibiotics in order to identify strategies to eliminate these persistent bacteria.

KEYWORDS:

• Antibiotic tolerance
• bacterial persistence
• host-pathogen interactions
• intracellular pathogen
• persistent infections
• Staphylococcus aureus
• small colony variants
• reactive oxygen species

Article highlights

• S. aureus survival inside host cells is associated with recurrent infections and systemic dissemination.

• S. aureus evolved a large array of mechanisms to elude phagocytosis by macrophages and neutrophils.

• S. aureus evolved a diversity of mechanisms to elude killing upon internalization by phagocytes: (i) oxidative stress, (ii) acidic pH, and (iii) antimicrobial peptides/proteins.

• Inside phagocytes, poor antibiotic activity results from a combination of factors: (i) poor intracellular pharmacokinetics and pharmacodynamics of antibiotics, (ii) induction of bacterial stress responses, and (iii) phenotypic switches to small colony variants or antibiotic persisters.

• Small colony variants and persisters share many similarities. Are the two phenotypes linked?

• Several promising strategies are in the pipeline to target intracellular pathogens.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

F.G. is supported by a Beware postdoctoral fellowship (project CRITIC) from the Region Wallonne, Belgium. F.V.B. is Research Director from the Belgian Fonds National de la recherche Scientifique (FNRS-FSR).