TY  - JOUR
A1  - Tuchscherr, Lorena
A1  - Bischoff, Markus
A1  - Lattar, Santiago M.
A1  - Noto Llana, Mariangeles
A1  - Pförtner, Henrike
A1  - Niemann, Silke
A1  - Geraci, Jennifer
A1  - Van de Vyver, Hélène
A1  - Fraunholz, Martin J.
A1  - Cheung, Ambrose L.
A1  - Herrmann, Mathias
A1  - Völker, Uwe
A1  - Sordelli, Daniel O.
A1  - Peters, Georg
A1  - Loeffler, Bettina
T1  - Sigma factor SigB is crucial to mediate Staphylococcus aureus adaptation during chronic infections
JF  - PLoS Pathogens
N2  - 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, \(\Delta\)sigB-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.
KW  - gene regulator agr
KW  - endothelial cells
KW  - modulates virulence
KW  - death pathway sar locus
KW  - factor B
KW  - small-colony variants
KW  - alpha-toxin
KW  - epithelial cells
KW  - in vitro
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143419
VL  - 11
IS  - 4
ER  -