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

PLoS Pathogens

Ambrose L. Cheung¹  Martin J. Fraunholz²  Henrike Pförtner³  Uwe Völker³  Mathias Herrmann⁴  Markus Bischoff⁴  Bettina Löffler⁵  Jennifer Geraci⁵  Lorena Tuchscherr⁵  Hélène Van de Vyver⁶  Silke Niemann⁶  Georg Peters⁶  Daniel O. Sordelli⁷  Santiago M. Lattar⁷  Mariangeles Noto Llana⁷ 

[1] Dartmouth Medical School, Hanover, New Hampshire, United States of America;Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany;Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany;Institute of Medical Microbiology and Hygiene, University of Saarland Medical Center, Homburg, Germany;Institute of Medical Microbiology, Jena University Hospital, Jena, Germany;Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany;Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM UBA-CONICET) y Facultad de Medicina, University of Buenos Aires, Buenos Aires, Argentina

关键词: Staphylococcus aureus;    Host cells;    Osteoblasts;    Intracellular pathogens;    Staphylococcal infection;    Virulence factors;    Cell death;    Endothelial cells;   

DOI  :  10.1371/journal.ppat.1004870

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY