Small Noncoding Rnas Controlling Pathogenesis Alejandro Toledo-Arana, Francis Repoila and Pascale Cossart

Small noncoding RNAs controlling pathogenesis Alejandro Toledo-Arana, Francis Repoila and Pascale Cossart Infectious diseases are a leading cause of mortality worldwide. biological processes, affecting all steps of gene expression A major challenge in achieving their eradication is a better [7]. In bacteria, sRNAs mostly function as coordinators understanding of bacterial pathogenesis processes. The recent of adaptation processes in response to environmental discovery of small noncoding RNAs (sRNAs) as modulators of changes, integrating environmental signals and control- gene expression in response to environmental cues has ling target gene expression [10–12]. Usually, sRNAs brought a new insight into bacterial regulation. sRNAs regulate gene expression either by pairing to mRNAs coordinate complex networks of stress adaptation and and affecting their stability and/or translation or by bind- virulence gene expression. sRNAs generally ensure such a ing to proteins and modifying their activity [7]. Here, we regulation by pairing to mRNAs of effector and/or regulatory focus on noncoding RNAs encoded by bacterial genomes genes, or by binding to proteins. An updated view on bacterial and demonstrated to regulate pathogenesis (Table 1)[1]. models responsible for important infections illustrates the key Other regulatory RNA elements, such as untranslated role of sRNAs in the control of pathogenesis mRNA regions or plasmidic sRNAs, have been reviewed Addresses elsewhere [3,5 ,7 ,13–15]. Institut Pasteur, Unite´ des Interactions Bacte´ ries-Cellules; INSERM, U604; and INRA, USC2020, Paris, F-75015, France RNAIII of Staphylococcus aureus, a paradigm for an sRNA controlling Corresponding author: Cossart, Pascale ([email protected]) expression of virulence factors Staphylococcus aureus is one of the most common causes of Current Opinion in Microbiology 2007, 10:182–188 nosocomial infections and toxin-mediated diseases. It expresses a large number of virulence factors, including This review comes from a themed issue on Cell regulation toxins, exoenzymes and extracellular matrix-binding sur- Edited by Gisela Storz and Dieter Haas face proteins. Numerous regulatory systems control the expression of these virulence factors [16]. Among these, Available online 23rd March 2007 the agr system seems to be the master regulator of S. aureus 1369-5274/$ – see front matter virulence. agr consists of two divergent transcription units, # 2006 Elsevier Ltd. All rights reserved. RNAII and RNAIII. RNAII encodes a typical two- component system (AgrA, the response regulator, and DOI 10.1016/j.mib.2007.03.004 AgrC, the sensor kinase), a propeptide AgrD and a pepti- dase AgrB. AgrB processes AgrD into a small autoinducing peptide, which binds to and activates AgrC. AgrA, AgrB, Introduction AgrC and AgrD constitute a quorum-sensing system During infection, pathogenic bacteria must be able to (QSS), with the higher concentration of the autoinducing express their virulence genes properly, and to survive peptide inducing the transcription of the divergent unit — in the environmental conditions imposed by their hosts. that is, RNAIII, the effector molecule of the agr system In general, the coordinated expression of genes involved in (Figure 1)[16]. RNAIII was the first regulatory sRNA virulence and adaptation to environmental cues is under discovered to be involved in bacterial pathogenesis [17]. the control of common regulatory cascades. Numerous RNAIII is a 514 nucleotide (nt) transcript folded into 14 proteins are involved in these regulatory pathways [1]. stem–loop structures, with a dual function: it encodes a 26 RNAs are also emerging as regulators, enabling the amino acid peptide, d-hemolysin (hld), and also acts as a pathogen to adapt its metabolic needs during infection regulatory sRNA controlling virulence. RNAIII is able to and to express its virulence genes when required. Among pair with at least three mRNA targets, for example hla, spa the RNA-based regulatory elements controlling pathogen- and rot mRNAs (Figure 2a,b). The 50-leader of hla mRNA, esis are riboswitches, 50-untranslated regions of mRNAs encoding a-hemolysin, can form a secondary structure that and small noncoding RNAs (sRNAs) [2,3,4,5,6]. occludes the ribosome-binding site (RBS). The 50-end of RNAIII, when binding to this folded hla mRNA structure, sRNAs — other than ribosomal RNAs (rRNAs) or transfer desequesters the RBS, thereby activating the translation of RNAs (tRNAs) — have been found in all organisms in the a-hemolysin mRNA (Figure 2a) [18]. The two other which they have been searched for (i.e. bacteria, archaea targets, spa and rot mRNA, which encode protein A and the and eukaryotes). In recent years, sRNAs have been transcription factor Rot, respectively, are negatively identified by different methods, and their number is affected by RNAIII, which pairs with and sequesters their constantly growing [7,8,9]. In addition, sRNAs have RBS [19,20]. The hybrid formed by RNAIII and spa been recognized as regulators involved in many important mRNA was shown to be a substrate for RNase III and a Current Opinion in Microbiology 2007, 10:182–188 www.sciencedirect.com Small noncoding RNAs controlling pathogenesis Toledo-Arana, Repoila and Cossart 183 Table 1 sRNAs involved in bacterial pathogenesis. Bacteria Diseases sRNA (nt) Target Refs Gram-positive bacteria Staphylococcus aureus Skin infections, bacteremia, endocarditis, osteomyelitis, toxin-mediated RNAIII (514) hla mRNA [18] diseases, abscesses, nosocomial infections spa mRNA [19] rot mRNA [20] SA1000 mRNA [21] Streptococcus pyogenes Pharyngitis, skin infections, acute rheumatic diseases, scarlet fever, FasX (300) ? [55] necrotizing fasciitis, glomerulonephritis Pel (459) ? [56] Clostridium perfringens Food poisoning, wound infections, gas gangrene VR RNA (400) ? [57] VirX (400) ? [58] Gram-negative bacteria Pseudomonas aeruginosa Burn and wound infections, endocarditis, cystitis, pneumonia in cystic RsmY (120) RsmA [27–29,34] fibrosis patients, septicaemia in immunocompromised patients RsmZ (119) Vibrio cholerae Cholera CsrB (417) CsrA [41] CsrC (366) CsrD (351) Qrr1 (96) hapR mRNA [40] Qrr2 (108) Qrr3 (107) Qrr4 (107) Salmonella typhimurium Gastroenteritis, enterocolitis, septicaemia in immunocompromised CsrB (350) CsrA [59] patients tmRNA (363) [60] Chlamydia trachomatis Sexually transmitted genital infections, trachoma IhtA (120) hctA mRNA? [44] target for degradation [19]. A similar situation has been present in the genome of the S. aureus N315 strain. sprD, proposed for the RNAIII–rot mRNA hybrid but further sprE, sprF and sprG sRNAs are encoded by the bacterio- investigation is required to establish fully the mode of phage fN315, also present in the N315 strain genome. action of RNAIII in this case [20]. Other mRNA targets of Interestingly, sprA, sprF and sprG are present in multiple RNAIII have been identified, including SA1000-mRNA, copies localized in other places of the genome and differ- which encodes an adhesin-like factor involved in adher- ent from SaPIn3 and fN315 [25]. sprA sRNA was shown ence and invasion of epithelial cells [21–23] (T Geissmann to pair with mRNAs encoding an ABC transporter operon, and P Romby, personal communication). including two ORFs (open reading frames; SA2216– SA2217) and a putative a-acetolactate decarboxylase Thus, RNAIII seems to be a paradigm in RNA-mediated (SA2007) [25], suggesting a possible modulation of the virulence gene expression. The agr-dependent expres- bacterial metabolism by a sRNA present in either a sion of virulence factors is subject to temporal control – pathogenicity island or a phage. However, it is not yet that is, during growth, adhesins (e.g. protein A) are known if some of the sprA–G sRNAs are involved in the produced before hemolysins (e.g. a-hemolysin and d- virulence of S. aureus. hemolysin), proteases and other degradative enzymes [16]. This sequence of events depends on various signals, RsmY and RsmZ sRNAs and the RsmA including cell density: when the cell number increases, translational repressor protein: a network the abundance of RNAIII also increases, resulting in controlling Pseudomonas aeruginosa decreased expression of adhesins (e.g. spa mRNA) and pathogenesis activation of translation of hemolysins (e.g. a-hemolysin Pseudomonas aeruginosa is a ubiquitous saprophyte and an and d-hemolysin). At the same time, through its trans- opportunistic human pathogen that causes severe infec- lation control of the transcription regulator Rot, RNAIII tions in immunocompromised patients. It forms biofilms also modulates the transcription of other genes involved on a variety of surfaces, including the lungs of cystic in virulence and metabolic adaptation [20,24]. There- fibrosis patients [26]. P. aeruginosa pathogenesis relies fore, the integration of the cell density signal by RNAIII mainly on the tightly regulated expression of a type III is a key process to regulate the expression of virulence secretion system, on biofilm (adherence) properties and traits in S. aureus in a time-dependent manner. on a large number of N-acyl-homoserine lactone- regulated extracellular toxins and secondary metabolites. Besides RNAIII, eleven other sRNAs have been ident- This control is based on numerous interlinked systems, ified in S. aureus. Among those, sprA, sprB and sprC are including the GacS-GacA–RsmY–Z-RsmA pathways localized in the pathogenicity island, SaPIn3, which is [27–30]. The GacS-GacA–RsmY–Z-RsmA network is www.sciencedirect.com Current Opinion in Microbiology 2007,

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