Abstract
The anaerobic Gram-positive bacterium Clostridium difficile causes intestinal infections responsible for symptoms ranging from mild diarrhea to fulminant colitis. Like other bacteria, C. difficile needs to sense and integrate environmental signals in order to adapt to changes and thrive in its environment. The second messenger cyclic diguanosine monophosphate (c-di-GMP) was recently recognized as a quasi-ubiquitous phenotype coordinator in bacteria. Mostly known to be involved in the transition from motile to sessile and multicellular behaviors in Gammaproteobacteria, c-di-GMP is now known to regulate many other phenotypes from cell morphogenesis to virulence, in many Gram-negative and a few Gram-positive bacteria. Herein, we review recent advances in our understanding of c-di-GMP signaling in the lifecycle of C. difficile.
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References
Abel S, Bucher T, Nicollier M, Hug I, Kaever V, Abel Zur Wiesch P, Jenal U (2013) Bi-modal distribution of the second messenger c-di-GMP controls cell fate and asymmetry during the caulobacter cell cycle. PLoS Genet 9:e1003744
Amikam D, Galperin MY (2006) PilZ domain is part of the bacterial c-di-GMP binding protein. Bioinformatics 22:3–6
Aubry A, Hussack G, Chen W, KuoLee R, Twine SM, Fulton KM, Foote S, Carrillo CD, Tanha J, Logan SM (2012) Modulation of toxin production by the flagellar regulon in Clostridium difficile. Infect Immun 80:3521–3532
Boehm A, Kaiser M, Li H, Spangler C, Kasper CA, Ackermann M, Kaever V, Sourjik V, Roth V, Jenal U (2010) Second messenger-mediated adjustment of bacterial swimming velocity. Cell 141:107–116
Bordeleau E, Brouillette E, Robichaud N, Burrus V (2010) Beyond antibiotic resistance: integrating conjugative elements of the SXT/R391 family that encode novel diguanylate cyclases participate to c-di-GMP signalling in Vibrio cholerae. Environ Microbiol 12:510–523
Bordeleau E, Fortier LC, Malouin F, Burrus V (2011) c-di-GMP turn-over in Clostridium difficile is controlled by a plethora of diguanylate cyclases and phosphodiesterases. PLoS Genet 7:e1002039
Bordeleau E, Purcell EB, Lafontaine DA, Fortier LC, Tamayo R, Burrus V (2015) Cyclic Di-GMP Riboswitch-Regulated Type IV Pili Contribute to Aggregation of Clostridium difficile. J Bacteriol 197:819–832
Breaker RR (2012) Riboswitches and the RNA world. Cold Spring Harb Perspect Biol 4
Burke KE, Lamont JT (2014) Clostridium difficile infection: a worldwide disease. Gut Liver 8:1–6
Buskila AA, Kannaiah S, Amster-Choder O (2014) RNA localization in bacteria. RNA Biol 11:1051–1060
Cafardi V, Biagini M, Martinelli M, Leuzzi R, Rubino JT, Cantini F, Norais N, Scarselli M, Serruto D, Unnikrishnan M (2013) Identification of a novel zinc metalloprotease through a global analysis of Clostridium difficile extracellular proteins. PLoS One 8:e81306
Chen Y, Chai Y, Guo JH, Losick R (2012) Evidence for cyclic Di-GMP-mediated signaling in Bacillus subtilis. J Bacteriol 194:5080–5090
Chen LH, Koseoglu VK, Guvener ZT, Myers-Morales T, Reed JM, D’Orazio SE, Miller KW, Gomelsky M (2014) Cyclic di-GMP-dependent signaling pathways in the pathogenic Firmicute Listeria monocytogenes. PLoS Pathog 10:e1004301
Duerig A, Abel S, Folcher M, Nicollier M, Schwede T, Amiot N, Giese B, Jenal U (2009) Second messenger-mediated spatiotemporal control of protein degradation regulates bacterial cell cycle progression. Genes Dev 23:93–104
El Meouche I, Peltier J, Monot M, Soutourina O, Pestel-Caron M, Dupuy B, Pons JL (2013) Characterization of the SigD regulon of C. difficile and its positive control of toxin production through the regulation of tcdR. PLoS One 8:e83748
Fang X, Gomelsky M (2010) A post-translational, c-di-GMP-dependent mechanism regulating flagellar motility. Mol Microbiol 76:1295–1305
Galperin MY, Higdon R, Kolker E (2010) Interplay of heritage and habitat in the distribution of bacterial signal transduction systems. Mol BioSyst 6:721–728
Gao X, Mukherjee S, Matthews PM, Hammad LA, Kearns DB, Dann CE 3rd (2013) Functional characterization of core components of the Bacillus subtilis cyclic-di-GMP signaling pathway. J Bacteriol 195:4782–4792
Gerding DN, Lessa FC (2015) The epidemiology of clostridium difficile infection inside and outside health care institutions. Infect Dis Clin North Am 29:37–50
Giltner CL, Nguyen Y, Burrows LL (2012) Type IV pilin proteins: versatile molecular modules. Microbiol Mol Biol Rev 76:740–772
Hengge R (2009) Principles of c-di-GMP signalling in bacteria. Nat Rev Microbiol 7:263–273
Hensbergen PJ, Klychnikov OI, Bakker D, van Winden VJ, Ras N, Kemp AC, Cordfunke RA, Dragan I, Deelder AM, Kuijper EJ, Corver J, Drijfhout JW, van Leeuwen HC (2014) A novel secreted metalloprotease (CD2830) from Clostridium difficile cleaves specific proline sequences in LPXTG cell surface proteins. Mol Cell Proteomics. doi:10.1074/mcp.M1113.034728 (in press)
Hisert KB, MacCoss M, Shiloh MU, Darwin KH, Singh S, Jones RA, Ehrt S, Zhang Z, Gaffney BL, Gandotra S, Holden DW, Murray D, Nathan C (2005) A glutamate-alanine-leucine (EAL) domain protein of Salmonella controls bacterial survival in mice, antioxidant defence and killing of macrophages: role of cyclic diGMP. Mol Microbiol 56:1234–1245
Holland LM, O’Donnell ST, Ryjenkov DA, Gomelsky L, Slater SR, Fey PD, Gomelsky M, O’Gara JP (2008) A staphylococcal GGDEF domain protein regulates biofilm formation independently of cyclic dimeric GMP. J Bacteriol 190:5178–5189
Hull TD, Ryu MH, Sullivan MJ, Johnson RC, Klena NT, Geiger RM, Gomelsky M, Bennett JA (2012) Cyclic Di-GMP phosphodiesterases RmdA and RmdB are involved in regulating colony morphology and development in Streptomyces coelicolor. J Bacteriol 194:4642–4651
Krasteva PV, Fong JC, Shikuma NJ, Beyhan S, Navarro MV, Yildiz FH, Sondermann H (2010) Vibrio cholerae VpsT regulates matrix production and motility by directly sensing cyclic di-GMP. Science 327:866–868
Kulasakara H, Lee V, Brencic A, Liberati N, Urbach J, Miyata S, Lee DG, Neely AN, Hyodo M, Hayakawa Y, Ausubel FM, Lory S (2006) Analysis of Pseudomonas aeruginosa diguanylate cyclases and phosphodiesterases reveals a role for bis-(3′-5′)-cyclic-GMP in virulence. Proc Natl Acad Sci 103:2839–2844
Lee ER, Baker JL, Weinberg Z, Sudarsan N, Breaker RR (2010) An allosteric self-splicing ribozyme triggered by a bacterial second messenger. Science 329:845–848
Massie JP, Reynolds EL, Koestler BJ, Cong JP, Agostoni M, Waters CM (2012) Quantification of high-specificity cyclic diguanylate signaling. Proc Natl Acad Sci 109:12746–12751
McKee RW, Mangalea MR, Purcell EB, Borchardt EK, Tamayo R (2013) The second messenger cyclic Di-GMP regulates clostridium difficile toxin production by controlling expression of sigD. J Bacteriol 195:5174–5185
Melville S, Craig L (2013) Type IV pili in Gram-positive bacteria. Microbiol Mol Biol Rev 77:323–341
Montero Llopis P, Jackson AF, Sliusarenko O, Surovtsev I, Heinritz J, Emonet T, Jacobs-Wagner C (2010) Spatial organization of the flow of genetic information in bacteria. Nature 466:77–81
Navarro MV, Newell PD, Krasteva PV, Chatterjee D, Madden DR, O’Toole GA, Sondermann H (2011) Structural basis for c-di-GMP-mediated inside-out signaling controlling periplasmic proteolysis. PLoS Biol 9:e1000588
Nevo-Dinur K, Nussbaum-Shochat A, Ben-Yehuda S, Amster-Choder O (2011) Translation-independent localization of mRNA in E. coli. Science 331:1081–1084
Newell PD, Monds RD, O’Toole GA (2009) LapD is a bis-(3′,5′)-cyclic dimeric GMP-binding protein that regulates surface attachment by Pseudomonas fluorescens Pf0-1. Proc Natl Acad Sci 106:3461–3466
Newell PD, Boyd CD, Sondermann H, O’Toole GA (2011) A c-di-GMP effector system controls cell adhesion by inside-out signaling and surface protein cleavage. PLoS Biol 9:e1000587
Paul K, Nieto V, Carlquist WC, Blair DF, Harshey RM (2010) The c-di-GMP binding protein YcgR controls flagellar motor direction and speed to affect chemotaxis by a “backstop brake” mechanism. Mol Cell 38:128–139
Proft T, Baker EN (2009) Pili in Gram-negative and Gram-positive bacteria–structure, assembly and their role in disease. Cell Mol Life Sci 66:613–635
Purcell EB, McKee RW, McBride SM, Waters CM, Tamayo R (2012) Cyclic diguanylate inversely regulates motility and aggregation in Clostridium difficile. J Bacteriol 194:3307–3316
Romling U, Gomelsky M, Galperin MY (2005) C-di-GMP: the dawning of a novel bacterial signalling system. Mol Microbiol 57:629–639
Romling U, Galperin MY, Gomelsky M (2013) Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev 77:1–52
Ross P, Weinhouse H, Aloni Y, Michaeli D, Weinberger-Ohana P, Mayer R, Braun S, de Vroom E, van der Marel GA, van Boom JH, Benziman M (1987) Regulation of cellulose synthesis in Acetobacter xylinum by cyclic diguanylic acid. Nature 325:279–281
Ryan RP, Fouhy Y, Lucey JF, Crossman LC, Spiro S, He YW, Zhang LH, Heeb S, Camara M, Williams P, Dow JM (2006) Cell-cell signaling in Xanthomonas campestris involves an HD-GYP domain protein that functions in cyclic di-GMP turnover. Proc Natl Acad Sci 103:6712–6717
Ryan RP, Fouhy Y, Lucey JF, Jiang BL, He YQ, Feng JX, Tang JL, Dow JM (2007) Cyclic di-GMP signalling in the virulence and environmental adaptation of Xanthomonas campestris. Mol Microbiol 63:429–442
Ryjenkov DA, Tarutina M, Moskvin OV, Gomelsky M (2005) Cyclic diguanylate is a ubiquitous signaling molecule in bacteria: insights into biochemistry of the GGDEF protein domain. J Bacteriol 187:1792–1798
Schmidt AJ, Ryjenkov DA, Gomelsky M (2005) The ubiquitous protein domain EAL is a cyclic diguanylate-specific phosphodiesterase: enzymatically active and inactive EAL domains. J Bacteriol 187:4774–4781
Sebaihia M, Wren BW, Mullany P, Fairweather NF, Minton N, Stabler R, Thomson NR, Roberts AP, Cerdeno-Tarraga AM, Wang H, Holden MT, Wright A, Churcher C, Quail MA, Baker S, Bason N, Brooks K, Chillingworth T, Cronin A, Davis P, Dowd L, Fraser A, Feltwell T, Hance Z, Holroyd S, Jagels K, Moule S, Mungall K, Price C, Rabbinowitsch E, Sharp S, Simmonds M, Stevens K, Unwin L, Whithead S, Dupuy B, Dougan G, Barrell B, Parkhill J (2006) The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat Genet 38:779–786
Serganov A, Nudler E (2013) A decade of riboswitches. Cell 152:17–24
Seshasayee AS, Fraser GM, Luscombe NM (2010) Comparative genomics of cyclic-di-GMP signalling in bacteria: post-translational regulation and catalytic activity. Nucleic Acids Res 38:5970–5981
Shang F, Xue T, Sun H, Xing L, Zhang S, Yang Z, Zhang L, Sun B (2009) The Staphylococcus aureus GGDEF domain-containing protein, GdpS, influences protein A gene expression in a cyclic diguanylic acid-independent manner. Infect Immun 77:2849–2856
Shen A (2012) Clostridium difficile toxins: mediators of inflammation. J Innate Immun 4:149–158
Soutourina OA, Monot M, Boudry P, Saujet L, Pichon C, Sismeiro O, Semenova E, Severinov K, Le Bouguenec C, Coppee JY, Dupuy B, Martin-Verstraete I (2013) Genome-wide identification of regulatory RNAs in the human pathogen Clostridium difficile. PLoS Genet 9:e1003493
Sudarsan N, Lee ER, Weinberg Z, Moy RH, Kim JN, Link KH, Breaker RR (2008) Riboswitches in eubacteria sense the second messenger cyclic di-GMP. Science 321:411–413
Tamayo R, Tischler AD, Camilli A (2005) The EAL domain protein VieA is a cyclic diguanylate phosphodiesterase. J Biol Chem 280:33324–33330
Tischler AD, Camilli A (2005) Cyclic diguanylate regulates Vibrio cholerae virulence gene expression. Infect Immun 73:5873–5882
Tulli L, Marchi S, Petracca R, Shaw HA, Fairweather NF, Scarselli M, Soriani M, Leuzzi R (2013) CbpA: a novel surface exposed adhesin of Clostridium difficile targeting human collagen. Cell Microbiol 15:1674–1687
Vedantam G, Clark A, Chu M, McQuade R, Mallozzi M, Viswanathan VK (2012) Clostridium difficile infection: toxins and non-toxin virulence factors, and their contributions to disease establishment and host response. Gut Microbes 3:121–134
Voth DE, Ballard JD (2005) Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 18:247–263
Yutin N, Galperin MY (2013) A genomic update on clostridial phylogeny: Gram-negative spore formers and other misplaced clostridia. Environ Microbiol 15:2631–2641
Acknowledgments
The authors are grateful to Alain Lavigueur for insightful comments on the manuscript. This work was supported by a Cystic Fibrosis Canada-Kin Canada Fellowship to E.B. V.B. holds a Canada Research Chair in Bacterial Molecular Genetics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Communicated by M. Kupiec.
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Bordeleau, E., Burrus, V. Cyclic-di-GMP signaling in the Gram-positive pathogen Clostridium difficile . Curr Genet 61, 497–502 (2015). https://doi.org/10.1007/s00294-015-0484-z
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DOI: https://doi.org/10.1007/s00294-015-0484-z