A defense-offense multi-layered regulatory switch in a pathogenic bacterium.

Mor Nitzan,Asaf Peer,Pascale Romby,Ofer Biham,Delphine Bronesky,Yael Altuvia,François Vandenesch,Pierre Fechter,Hanah Margalit

doi:10.1093/nar/gkv001

Abstract

Cells adapt to environmental changes by efficiently adjusting gene expression programs. Staphylococcus aureus, an opportunistic pathogenic bacterium, switches between defensive and offensive modes in response to quorum sensing signal. We identified and studied the structural characteristics and dynamic properties of the core regulatory circuit governing this switch by deterministic and stochastic computational methods, as well as experimentally. This module, termed here Double Selector Switch (DSS), comprises the RNA regulator RNAIII and the transcription factor Rot, defining a double-layered switch involving both transcriptional and post-transcriptional regulations. It coordinates the inverse expression of two sets of target genes, immuno-modulators and exotoxins, expressed during the defensive and offensive modes, respectively. Our computational and experimental analyses show that the DSS guarantees fine-tuned coordination of the inverse expression of its two gene sets, tight regulation, and filtering of noisy signals. We also identified variants of this circuit in other bacterial systems, suggesting it is used as a molecular switch in various cellular contexts and offering its use as a template for an effective switching device in synthetic biology studies.

Highlights

Bacteria may undergo major transitions during their cellular life, such as transitions between aerobic and anaerobic metabolism, between motile and sessile lifestyles or between colonization and dissemination in case of bacterial pathogens
We identified and analyzed an elaborate switching module termed the Double Selector Switch (DSS) (Figure 1) within the complex regulatory network of S. aureus, comprising a regulatory small RNAs (sRNAs) and a transcription factor, which governs
We showed that the DSS exhibits special dynamical properties as a switching device not exhibited by simpler switches that compose it

Summary

Introduction

Bacteria may undergo major transitions during their cellular life, such as transitions between aerobic and anaerobic metabolism, between motile and sessile lifestyles or between colonization and dissemination (or spreading) in case of bacterial pathogens. In the offensive mode the bacteria secrete toxins such as superantigens that stimulate the immune system, exfoliative toxins promoting intradermal cleavage, and pore-forming toxins that form tunnels and pores in the membranes of the host cells (referred to as offensive genes) [22]. The expression of these accessory factors is highly coordinated and is closely linked to the metabolism and biological requirements of S. aureus [24]. The two-layered switch we identified includes two regulators (Figure 1): (i) the transcription factor Rot, which is active when cell density is low,

Methods

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Conclusion