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

English version České info

Staphylococcus aureus is a commensal and an opportunistic pathogen that causes a large range of community and hospital-acquired infections. The bacteria produce an array of virulence factors, the expression of which is regulated by a set of regulators including proteins and RNAs. In recent years, 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. This study shows that RsaA, a staphylococcal conserved non-coding RNA, operates at the post-transcriptional level by repressing the translation of the master regulatory protein MgrA. The repression is based on a direct interaction of RsaA with the ribosome binding site of mgrA mRNA. Through MgrA regulation, RsaA activates biofilm formation and inhibits capsule synthesis. Using appropriate animal models, we showed that RsaA acts as a suppressor of virulence because the deletion of its gene increases the invasiveness of S. aureus in the mice sepsis model. RsaA is thus part of complex regulatory network that modify the interactions of S. aureus with the eukaryotic immune system. These findings illustrate how small RNAs can have a major impact in bacterial biology.

Vyšlo v časopise: A Non-Coding RNA Promotes Bacterial Persistence and Decreases Virulence by Regulating a Regulator in. PLoS Pathog 10(3): e32767. doi:10.1371/journal.ppat.1003979
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003979

Souhrn

Zdroje

1. ChambersHF, DeleoFR (2009) Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 7 : 629–641.

2. PriestNK, RudkinJK, FeilEJ, van den ElsenJM, CheungA, et al. (2012) From genotype to phenotype: can systems biology be used to predict Staphylococcus aureus virulence? Nat Rev Microbiol 10 : 791–797.

3. NovickRP, GeisingerE (2008) Quorum sensing in staphylococci. Annu Rev Genet 42 : 541–564.

4. FeldenB, VandeneschF, BoulocP, RombyP (2011) The Staphylococcus aureus RNome and its commitment to virulence. PLoS Pathog 7: e1002006.

5. RomillyC, CaldelariI, ParmentierD, LioliouE, RombyP, et al. (2012) Current knowledge on regulatory RNAs and their machineries in Staphylococcus aureus. RNA Biol 9 : 402–413.

6. NovickRP, RossHF, ProjanSJ, KornblumJ, KreiswirthB, et al. (1993) Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J 12 : 3967–3975.

7. MorfeldtE, TaylorD, von GabainA, ArvidsonS (1995) Activation of alpha-toxin translation in Staphylococcus aureus by the trans-encoded antisense RNA, RNAIII. EMBO J 14 : 4569–4577.

8. GeisingerE, AdhikariRP, JinR, RossHF, NovickRP (2006) Inhibition of rot translation by RNAIII, a key feature of agr function. Mol Microbiol 61 : 1038–1048.

9. HuntzingerE, BoissetS, SaveanuC, BenitoY, GeissmannT, et al. (2005) Staphylococcus aureus RNAIII and the endoribonuclease III coordinately regulate spa gene expression. EMBO J 24 : 824–835.

10. BoissetS, GeissmannT, HuntzingerE, FechterP, BendridiN, et al. (2007) Staphylococcus aureus RNAIII coordinately represses the synthesis of virulence factors and the transcription regulator Rot by an antisense mechanism. Genes Dev 21 : 1353–1366.

11. ChevalierC, BoissetS, RomillyC, MasquidaB, FechterP, et al. (2010) Staphylococcus aureus RNAIII binds to two distant regions of coa mRNA to arrest translation and promote mRNA degradation. PLoS Pathog 6: e1000809.

12. PichonC, FeldenB (2005) Small RNA genes expressed from Staphylococcus aureus genomic and pathogenicity islands with specific expression among pathogenic strains. Proc Natl Acad Sci USA 102 : 14249–14254.

13. RobertsC, AndersonKL, MurphyE, ProjanSJ, MountsW, et al. (2006) Characterizing the effect of the Staphylococcus aureus virulence factor regulator, SarA, on log-phase mRNA half-lives. J Bacteriol 188 : 2593–2603.

14. BeaumeM, HernandezD, FarinelliL, DeluenC, LinderP, et al. (2010) Cartography of methicillin-resistant S. aureus transcripts: detection, orientation and temporal expression during growth phase and stress conditions. PLoS One 5: e10725.

15. NielsenJS, LarsenMH, LillebaekEM, BergholzTM, ChristiansenMH, et al. (2011) A small RNA controls expression of the chitinase ChiA in Listeria monocytogenes. PLoS One 6: e19019.

16. SayedN, JousselinA, FeldenB (2012) A cis-antisense RNA acts in trans in Staphylococcus aureus to control translation of a human cytolytic peptide. Nat Struct Mol Biol 19 : 105–112.

17. SayedN, Nonin-LecomteS, RetyS, FeldenB (2012) Functional and structural insights of a Staphylococcus aureus apoptotic-like membrane peptide from a toxin-antitoxin module. J Biol Chem 287 : 43454–43463.

18. HowdenBP, BeaumeM, HarrisonPF, HernandezD, SchrenzelJ, et al. (2013) Analysis of the small RNA transcriptional response in multidrug-resistant Staphylococcus aureus after antimicrobial exposure. Antimicrob Agents Chemother 57 : 3864–3874.

19. Abu-QatousehLF, ChinniSV, SeggewissJ, ProctorRA, BrosiusJ, et al. (2010) Identification of differentially expressed small non-protein-coding RNAs in Staphylococcus aureus displaying both the normal and the small-colony variant phenotype. J Mol Med (Berl) 88 : 565–575.

20. GeissmannT, MarziS, RombyP (2009) The role of mRNA structure in translational control in bacteria. RNA Biol 6 : 153–160.

21. BohnC, RigoulayC, ChabelskayaS, SharmaCM, MarchaisA, et al. (2010) Experimental discovery of small RNAs in Staphylococcus aureus reveals a riboregulator of central metabolism. Nucleic Acids Res 38 : 6620–6636.

22. LasaI, Toledo-AranaA, DobinA, VillanuevaM, de los MozosIR, et al. (2011) Genome-wide antisense transcription drives mRNA processing in bacteria. Proc Natl Acad Sci USA 108 : 20172–20177.

23. LioliouE, SharmaCM, CaldelariI, HelferAC, FechterP, et al. (2012) Global regulatory functions of the Staphylococcus aureus endoribonuclease III in gene expression. PLoS Genet 8: e1002782.

24. LuongTT, NewellSW, LeeCY (2003) Mgr, a novel global regulator in Staphylococcus aureus. J Bacteriol 185 : 3703–3710.

25. IngavaleS, van WamelW, LuongTT, LeeCY, CheungAL (2005) Rat/MgrA, a regulator of autolysis, is a regulator of virulence genes in Staphylococcus aureus. Infect Immun 73 : 1423–1431.

26. LuongTT, DunmanPM, MurphyE, ProjanSJ, LeeCY (2006) Transcription Profiling of the mgrA Regulon in Staphylococcus aureus. J Bacteriol 188 : 1899–1910.

27. IngavaleSS, Van WamelW, CheungAL (2003) Characterization of RAT, an autolysis regulator in Staphylococcus aureus. Mol Microbiol 48 : 1451–1466.

28. GuptaRK, AlbaJ, XiongYQ, BayerAS, LeeCY (2013) MgrA activates expression of capsule genes, but not the alpha-toxin gene in experimental Staphylococcus aureus endocarditis. J Infect Dis

29. MeierS, GoerkeC, WolzC, SeidlK, HomerovaD, et al. (2007) sigmaB and the sigmaB-dependent arlRS and yabJ-spoVG loci affect capsule formation in Staphylococcus aureus. Infect Immun 75 : 4562–4571.

30. BuschA, RichterAS, BackofenR (2008) IntaRNA: efficient prediction of bacterial sRNA targets incorporating target site accessibility and seed regions. Bioinformatics 24 : 2849–2856.

31. TjadenB (2008) TargetRNA: a tool for predicting targets of small RNA action in bacteria. Nucleic Acids Res 36: W109–13.

32. TrotondaMP, TamberS, MemmiG, CheungAL (2008) MgrA represses biofilm formation in Staphylococcus aureus. Infect Immun 76 : 5645–5654.

33. LuongTT, LeeCY (2006) The arl locus positively regulates Staphylococcus aureus type 5 capsule via an mgrA-dependent pathway. Microbiology 152 : 3123–3131.

34. VuongC, VoyichJM, FischerER, BraughtonKR, WhitneyAR, et al. (2004) Polysaccharide intercellular adhesin (PIA) protects Staphylococcus epidermidis against major components of the human innate immune system. Cell Microbiol 6 : 269–275.

35. ThakkerM, ParkJS, CareyV, LeeJC (1998) Staphylococcus aureus serotype 5 capsular polysaccharide is antiphagocytic and enhances bacterial virulence in a murine bacteremia model. Infect Immun 66 : 5183–5189.

36. XuS, ArbeitRD, LeeJC (1992) Phagocytic killing of encapsulated and microencapsulated Staphylococcus aureus by human polymorphonuclear leukocytes. Infect Immun 60 : 1358–1362.

37. MarincolaG, SchaferT, BehlerJ, BernhardtJ, OhlsenK, et al. (2012) RNase Y of Staphylococcus aureus and its role in the activation of virulence genes. Mol Microbiol 85 : 817–832.

38. BallalA, MannaAC (2009) Expression of the sarA family of genes in different strains of Staphylococcus aureus. Microbiology 155 : 2342–2352.

39. WagnerEG, AltuviaS, RombyP (2002) Antisense RNAs in bacteria and their genetic elements. Adv Genet 46 : 361–398.

40. LioliouE, SharmaCM, AltuviaY, CaldelariI, RomillyC, et al. (2013) In vivo mapping of RNA-RNA interactions in Staphylococcus aureus using the endoribonuclease III. Methods 63 : 135–143.

41. BischoffM, DunmanP, KormanecJ, MacapagalD, MurphyE, et al. (2004) Microarray-based analysis of the Staphylococcus aureus sigmaB regulon. J Bacteriol 186 : 4085–4099.

42. RashidMH, RumbaughK, PassadorL, DaviesDG, HamoodAN, et al. (2000) Polyphosphate kinase is essential for biofilm development, quorum sensing, and virulence of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 97 : 9636–9641.

43. ValleJ, Toledo-AranaA, BerasainC, GhigoJM, AmorenaB, et al. (2003) SarA and not sigmaB is essential for biofilm development by Staphylococcus aureus. Mol Microbiol 48 : 1075–1087.

44. SunF, DingY, JiQ, LiangZ, DengX, et al. (2012) Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance. Proc Natl Acad Sci USA 109 : 15461–15466.

45. MoscosoM, GarciaE, LopezR (2006) Biofilm formation by Streptococcus pneumoniae: role of choline, extracellular DNA, and capsular polysaccharide in microbial accretion. J Bacteriol 188 : 7785–7795.

46. FlahautS, VinogradovE, KelleyKA, BrennanS, HiramatsuK, et al. (2008) Structural and biological characterization of a capsular polysaccharide produced by Staphylococcus haemolyticus. J Bacteriol 190 : 1649–1657.

47. NovickRP, ChristieGE, PenadesJR (2010) The phage-related chromosomal islands of Gram-positive bacteria. Nat Rev Microbiol 8 : 541–551.

48. MaurelliAT (2007) Black holes, antivirulence genes, and gene inactivation in the evolution of bacterial pathogens. FEMS Microbiol Lett 267 : 1–8.

49. BlivenKA, MaurelliAT (2012) Antivirulence genes: insights into pathogen evolution through gene loss. Infect Immun 80 : 4061–4070.

50. Toledo-AranaA, DussurgetO, NikitasG, SestoN, Guet-RevilletH, et al. (2009) The Listeria transcriptional landscape from saprophytism to virulence. Nature 459 : 950–956.

51. BaekCH, WangS, RolandKL, CurtissRr (2009) Leucine-responsive regulatory protein (Lrp) acts as a virulence repressor in Salmonella enterica serovar Typhimurium. J Bacteriol 191 : 1278–1292.

52. LeeEJ, GroismanEA (2010) An antisense RNA that governs the expression kinetics of a multifunctional virulence gene. Mol Microbiol 76 : 1020–1033.

53. SongJ, LaysC, VandeneschF, BenitoY, BesM, et al. (2012) The expression of small regulatory RNAs in clinical samples reflects the different life styles of Staphylococcus aureus in colonization vs. infection. PLoS One 7: e37294.

54. KreiswirthBN, LofdahlS, BetleyMJ, O'ReillyM, SchlievertPM, et al. (1983) The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophage. Nature 305 : 709–712.

55. ArnaudM, ChastanetA, DebarbouilleM (2004) New vector for efficient allelic replacement in naturally nontransformable, low-GC-content, gram-positive bacteria. Appl Environ Microbiol 70 : 6887–6891.

56. ChevalierC, GeissmannT, HelferAC, RombyP (2009) Probing mRNA structure and sRNA-mRNA interactions in bacteria using enzymes and lead(II). Methods Mol Biol 540 : 215–232.

57. FechterP, ChevalierC, YusupovaG, YusupovM, RombyP, et al. (2009) Ribosomal initiation complexes probed by toeprinting and effect of trans-acting translational regulators in bacteria. Methods Mol Biol 540 : 247–263.

58. HeilmannC, SchweitzerO, GerkeC, VanittanakomN, MackD, et al. (1996) Molecular basis of intercellular adhesion in the biofilm-forming Staphylococcus epidermidis. Mol Microbiol 20 : 1083–1091.

59. ChavantP, Gaillard-MartinieB, TalonR, HebraudM, BernardiT (2007) A new device for rapid evaluation of biofilm formation potential by bacteria. J Microbiol Methods 68 : 605–612.

60. CucarellaC, SolanoC, ValleJ, AmorenaB, LasaI, et al. (2001) Bap, a Staphylococcus aureus surface protein involved in biofilm formation. J Bacteriol 183 : 2888–2896.

61. KristianSA, BirkenstockTA, SauderU, MackD, GotzF, et al. (2008) Biofilm formation induces C3a release and protects Staphylococcus aureus from IgG and complement deposition and from neutrophil-dependent killing. J Infect Dis 197 : 1028–1035.