Abstract
Staphylococcus aureus is a major human pathogen that causes a range of infections from acute invasive to chronic and difficult-to-treat. Infection strategies associated with persisting S. aureus infections are bacterial host cell invasion and the bacterial ability to dynamically change phenotypes from the aggressive wild-type to small colony variants (SCVs), which are adapted for intracellular long-term persistence. The underlying mechanisms of the bacterial switching and adaptation mechanisms appear to be very dynamic, but are largely unknown. Here, we analyzed the role and the crosstalk of the global S. aureus regulators agr, sarA and SigB by generating single, double and triple mutants, and testing them with proteome analysis and in different in vitro and in vivo infection models. We were able to demonstrate that SigB is the crucial factor for adaptation in chronic infections. During acute infection, the bacteria require the simultaneous action of the agr and sarA loci to defend against invading immune cells by causing inflammation and cytotoxicity and to escape from phagosomes in their host cells that enable them to settle an infection at high bacterial density. To persist intracellularly the bacteria subsequently need to silence agr and sarA. Indeed agr and sarA deletion mutants expressed a much lower number of virulence factors and could persist at high numbers intracellularly. SigB plays a crucial function to promote bacterial intracellular persistence. In fact, ΔsigB-mutants did not generate SCVs and were completely cleared by the host cells within a few days. In this study we identified SigB as an essential factor that enables the bacteria to switch from the highly aggressive phenotype that settles an acute infection to a silent SCV-phenotype that allows for long-term intracellular persistence. Consequently, the SigB-operon represents a possible target to develop preventive and therapeutic strategies against chronic and therapy-refractory infections.
Highlights
S. aureus is a major human pathogen that can infect almost every organ in the body and cause destructive infections [1]
Staphylococcus aureus is a frequent pathogen of severe invasive infections that can develop into chronicity and become extremely difficult to eradicate
Chronic infections have been highly associated with altered bacterial phenotypes, i.e., the small colony variants (SCVs) that dynamically appear after bacterial host cell invasion and are highly adapted for intracellular long-term persistence
Summary
S. aureus is a major human pathogen that can infect almost every organ in the body and cause destructive infections [1]. We demonstrated that S. aureus can dynamically switch phenotypes from a highly aggressive and cytotoxic wild-type form to a metabolically inactive phenotype (small colony variants, SCVs) that is able to persist for long time periods within host cells without provoking a response from the host immune system [9]. In their intracellular location the bacteria are most likely very well protected from antimicrobial treatments and the hosts defense system. The adaptation mechanisms involved and how bacteria cope with this stress, are largely unknown, but probably involve global changes in gene expression to promote survival
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
