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

TUCHSCHERR, LORENA; BISCHOFF M; LATTAR, SANTIAGO; NOTO LLANA M; PFÖRTNER H; NIEMANN S; GERACI J; VAN DE VYVER H; FRAUNHOLZ MJ; CHEUNG AL; HERRMANN M; VÖLKER U; SORDELLI DO; PETERS G; LÖFFLER B

PLOS PATHOGENS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2015

1553-7366

Staphylococcus aureus is a major human pathogen that causes a range of infections fromacute invasive to chronic and difficult-to-treat. Infection strategies associated with persistingS. aureus infections are bacterial host cell invasion and the bacterial ability to dynamicallychange phenotypes from the aggressive wild-type to small colony variants (SCVs), whichare adapted for intracellular long-term persistence. The underlying mechanisms of the bacterialswitching 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 proteomeanalysis and in different in vitro and in vivo infection models. We were able to demonstratethat SigB is the crucial factor for adaptation in chronic infections. During acuteinfection, the bacteria require the simultaneous action of the agr and sarA loci to defendagainst invading immune cells by causing inflammation and cytotoxicity and to escape fromphagosomes 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. Indeedagr and sarA deletion mutants expressed a much lower number of virulence factors andcould persist at high numbers intracellularly. SigB plays a crucial function to promote bacterialintracellular persistence. In fact, ΔsigB-mutants did not generate SCVs and werecompletely cleared by the host cells within a few days. In this study we identified SigB as anessential factor that enables the bacteria to switch from the highly aggressive phenotypethat settles an acute infection to a silent SCV-phenotype that allows for long-term intracellularpersistence. Consequently, the SigB-operon represents a possible target to develop preventiveand therapeutic strategies against chronic and therapy-refractory infections