A Non-Coding RNA Promotes Bacterial Persistence and Decreases Virulence by Regulating a Regulator in Staphylococcus aureus

Cédric Romilly,Thomas Geissmann,François Vandenesch,Pascale Romby,Claire Lays,Isabelle Caldelari,Arnaud Tomasini,Yvonne Benito,Sandrine Boisset,Philippe Hammann

doi:10.1371/journal.ppat.1003979

Abstract

Staphylococcus aureus produces a high number of RNAs for which the functions are poorly understood. Several non-coding RNAs carry a C-rich sequence suggesting that they regulate mRNAs at the post-transcriptional level. We demonstrate that the Sigma B-dependent RsaA RNA represses the synthesis of the global transcriptional regulator MgrA by forming an imperfect duplex with the Shine and Dalgarno sequence and a loop-loop interaction within the coding region of the target mRNA. These two recognition sites are required for translation repression. Consequently, RsaA causes enhanced production of biofilm and a decreased synthesis of capsule formation in several strain backgrounds. These phenotypes led to a decreased protection of S. aureus against opsonophagocytic killing by polymorphonuclear leukocytes compared to the mutant strains lacking RsaA. Mice animal models showed that RsaA attenuates the severity of acute systemic infections and enhances chronic catheter infection. RsaA takes part in a regulatory network that contributes to the complex interactions of S. aureus with the host immune system to moderate invasiveness and favour chronic infections. It is the first example of a conserved small RNA in S. aureus functioning as a virulence suppressor of acute infections. Because S. aureus is essentially a human commensal, we propose that RsaA has been positively selected through evolution to support commensalism and saprophytic interactions with the host.

Highlights

Staphylococcus aureus is an opportunistic pathogen that has evolved complex regulatory circuits allowing rapid adaption of cell growth in response to its diverse hosts and ecological niches
The bacteria produce an array of virulence factors, the expression of which is regulated by a set of regulators including proteins and RNAs
A large number of small non-coding RNAs encoded by the S. aureus genome have been identified but determination of their function is still lagging behind

Summary

Introduction

Staphylococcus aureus is an opportunistic pathogen that has evolved complex regulatory circuits allowing rapid adaption of cell growth in response to its diverse hosts and ecological niches. Several teams have experimentally identified a large number of small RNAs (sRNA) that are issued from the core genome and from mobile and accessory elements (e.g., [12,13]). These sRNAs include cis-acting regulatory regions of mRNAs (the so-called riboswitches), cis-encoding antisense RNAs (asRNA), and non-coding RNAs (ncRNAs). The functional and mechanistic studies of trans-acting sRNAs are still lagging behind their discovery, but some of them are known to sense population density and various environmental changes, modify cell surface properties, adjust the bacterial metabolism during cell growth, regulate virulence gene expression, and respond to antibiotic treatment [4,18]

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