Sigma Factor SigB Is Crucial to Mediate Staphylococcus aureus Adaptation during Chronic Infections

PLoS Pathog. 2015 Apr 29;11(4):e1004870. doi: 10.1371/journal.ppat.1004870. eCollection 2015 Apr.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Line
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / microbiology*
  • Endothelium, Vascular / pathology
  • Gene Deletion
  • Host-Pathogen Interactions*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / immunology
  • Human Umbilical Vein Endothelial Cells / microbiology
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mutation
  • Neutrophils / cytology
  • Neutrophils / immunology
  • Neutrophils / microbiology*
  • Neutrophils / pathology
  • Osteoblasts / cytology
  • Osteoblasts / immunology
  • Osteoblasts / microbiology*
  • Osteoblasts / pathology
  • Proteomics
  • Sigma Factor / genetics
  • Sigma Factor / metabolism*
  • Staphylococcal Infections / immunology
  • Staphylococcal Infections / metabolism
  • Staphylococcal Infections / microbiology*
  • Staphylococcal Infections / pathology
  • Staphylococcus aureus / immunology
  • Staphylococcus aureus / metabolism
  • Staphylococcus aureus / physiology*
  • Time Factors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Agr protein, Staphylococcus aureus
  • Bacterial Proteins
  • SarA protein, Staphylococcus aureus
  • SigB protein, Bacteria
  • Sigma Factor
  • Trans-Activators

Grant support

This work was supported by grants of the Transregional Collaborative Research Centre 34 (C12; http://www.staphaureus.org), of the IZKF (Löf2/030/10; http://campus.uni-muenster.de/izkf.html) and by the EXE 1003 - CiM (http://www.uni-muenster.de/Cells-in-Motion/de) to BL. LT was supported by a grant from DAAD-MINCyT PROALAR 57161981 (DA-13-06) (http://www.daad.org.ar/es/22137/index.html). DOS was supported by grants from ANPCyT 2013-00941 and UBACyT 20020130100331BA (http://www.uba.ar/secyt). MB was supported by the DFG grant BI 1350/1-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.