Abstract
Quorum sensing (QS), a cell-to-cell communication process, is widely distributed in the bacterial kingdom. Bacteria use QS to control gene expression in response to cell density by detecting the signal molecules called autoinducers. AphA protein is the master QS regulator of vibrios operating at low cell density. It regulates the expression of a variety of genes, especially those encoding virulence factors, flagella/motility and biofilm formation. The role and regulation of AphA in vibrios, especially in human pathogenic vibrios, are summarized in this review. Clarification of the roles of AphA will help us to understand the pathogenesis of vibrios.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Seasonality of chesapeake bay bacterioplankton species. Appl. Environ. Microb. 68(11), 5488–5497 (2002).
- 2 . Role of non-coding regulatory RNA in the virulence of human pathogenic Vibrios. Front. Microbiol. 7, 2160 (2016).
- 3 . Biodiversity of vibrios. Microbiol. Mol. Biol. R. 68(3), 403–431 (2004).
- 4 . Quorum sensing and expression of virulence in Escherichia coli O157:H7. Int. J. Food. Microbiol. 85(1–2), 1–9 (2003).
- 5 . Quorum sensing gene regulation by LuxR/HapR master regulators in vibrios. J. Bacteriol. 199(19), e00105–e00117 (2017).
- 6 . A genetic analysis of the function of LuxO, a two-component response regulator involved in quorum sensing in Vibrio harveyi. Mol. Microbiol. 31(2), 665–677 (2010).
- 7 . Multiple small RNAs act additively to integrate sensory information and control quorum sensing in Vibrio harveyi. Gene. Dev. 21(2), 221–233 (2007).
- 8 Molecular characterization of direct target genes and cis-acting consensus recognized by quorum-sensing regulator AphA in Vibrio parahaemolyticus. PLoS ONE 7(9), e44210 (2012). •• An imperfect inverted repeat of ATATGC with a 6-nt centered spacer was generated as the AphA binding consensus.
- 9 . Quorum-sensing non-coding small RNAs use unique pairing regions to differentially control mRNA targets. Mol. Microbiol. 83(3), 599–611 (2012). • Regulation of AphA production by the Qrr sRNAs was elucidated.
- 10 . AphA and LuxR/HapR reciprocally control quorum sensing in Vibrios. Gene. Dev. 25(4), 397–408 (2011).
- 11 . Transcriptional regulation of opaR, qrr2-4 and aphA by the master quorum-sensing regulator OpaR in Vibrio parahaemolyticus. PLoS ONE 7(4), e34622 (2012).
- 12 . The small RNA chaperone Hfq and multiple small RNAs control quorum sensing in Vibrio harveyi and Vibrio cholerae. Cell 118(1), 69–82 (2004).
- 13 . The Vibrio harveyi quorum-sensing system uses shared regulatory components to discriminate between multiple autoinducers. Gene Dev. 20(19), 2754–2767 (2006).
- 14 . A negative feedback loop involving small RNAs accelerates Vibrio cholerae's transition out of quorum-sensing mode. Gene Dev. 22(2), 226–238 (2008). • Elucidated the signal transduction of quorum sensing in Vibrio cholerae.
- 15 . A small-RNA-mediated negative feedback loop controls quorum-sensing dynamics in Vibrio harveyi. Mol. Microbiol. 70(4), 896–907 (2008). • Elucidated the signal transduction of quorum sensing in V. harveyi.
- 16 . Mechanisms underlying the additive and redundant Qrr phenotypes in Vibrio harveyi and Vibrio cholerae. J. Theor. Biol. 340, 38–49 (2014).
- 17 A qrr noncoding RNA deploys four different regulatory mechanisms to optimize quorum-sensing dynamics. Cell 160(1–2), 228–240 (2015).
- 18 . Iron- and quorum-sensing signals converge on small quorum-regulatory RNAs for coordinated regulation of virulence factors in Vibrio vulnificus. J. Biol. Chem. 291(27), 14213–14230 (2016).
- 19 . Individual and combined roles of the master regulators AphA and LuxR in control of the Vibrio harveyi quorum-sensing regulon. J. Bacteriol. 195(3), 436–443 (2013).
- 20 . Chromatin immunoprecipitation sequencing technology reveals global regulatory roles of low-cell-density quorum-sensing regulator AphA in the pathogen Vibrio alginolyticus. J. Bacteriol. 198(21), 2985–2999 (2016). • A new strategy to investigate the regulon of a regulator.
- 21 . Crystal structure of the virulence gene activator AphA from Vibrio cholerae reveals it is a novel member of the winged helix transcription factor superfamily. J. Biol. Chem. 280(14), 13779–13783 (2005). •• The 2.2-Å x-ray crystal structure of the AphA dimer was determined.
- 22 . Vibrio cholerae AphA uses a novel mechanism for virulence gene activation that involves interaction with the LysR-type regulator AphB at the tcpPH promoter. Mol. Microbiol. 53(1), 129–142 (2004).
- 23 Genome sequence of Vibrio parahaemolyticus: a pathogenic mechanism distinct from that of V cholerae. Lancet 361(9359), 743–749 (2003).
- 24 Comparative genomic analyses identify the Vibrio harveyi genome sequenced strains BAA-1116 and HY01 as Vibrio campbellii. Env. Microbiol. Rep. 2(1), 81–89 (2010).
- 25 Comparative genome analysis of Vibrio vulnificus, a marine pathogen. Genome Res. 13(12), 2577–2587 (2004).
- 26 Genome sequence of Vibrio splendidus: an abundant planctonic marine species with a large genotypic diversity. Environ. Microbiol. 11(8), 1959–1970 (2010).
- 27 DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae. Nature 406, 477–483 (2000).
- 28 . Complete genome sequence of the marine fish pathogen Vibrio anguillarum harboring the pJM1 virulence plasmid and genomic comparison with other virulent strains of V. anguillarum and V. ordalii. Infect. Immun. 79(7), 2889 (2011).
- 29 . The Vibrio harveyi master quorum-sensing regulator, LuxR, a TetR-type protein is both an activator and a repressor: DNA recognition and binding specificity at target promoters. Mol. Microbiol. 70(1), 76 (2008).
- 30 . The quorum sensing regulator HapR downregulates the expression of the virulence gene transcription factor AphA in Vibrio cholerae by antagonizing Lrp- and VpsR-mediated activation. Mol. Microbiol. 64(4), 953 (2007).
- 31 . Regulation of virulence gene expression in Vibrio cholerae by quorum sensing: HapR functions at the aphA promoter. Mol. Microbiol. 46(4), 1135 (2002).
- 32 . Vibrio cholerae ToxR downregulates virulence factor production in response to cyclo(Phe-Pro). mBio. 4(5), e00366–e00313 (2013).
- 33 . Integration of cyclic di-GMP and quorum sensing in the control of vpsT and aphA in Vibrio cholerae. J. Bacteriol. 193(22), 6331–6341 (2011).
- 34 . Quorum sensing controls biofilm formation in Vibrio cholerae through modulation of cyclic di-GMP levels and repression of vpsT. J. Bacteriol. 190(7), 2527–2536 (2008).
- 35 Targeting aphA: a new high-throughput screening assay identifies compounds that reduce prime virulence factors of Vibrio cholerae. J. Med. Microbiol. 65(7), 678 (2016). •• A new strategy to screen new drugs for preventing vibrio infections.
- 36 . The surprisingly diverse ways that prokaryotes move. Nat. Rev. Microbiol. 6(6), 466–476 (2008).
- 37 . Isolation of the polar and lateral flagellum-defective mutants in Vibrio alginolyticus and identification of their flagellar driving energy sources. J. Bacteriol. 177(17), 5158–5160 (1995).
- 38 . Polar flagellar motility of the Vibrionaceae. Microbiol. Mol. Biol. R. 65(3), 445–462 (2001).
- 39 AphA is required for biofilm formation, motility and virulence in pandemic Vibrio parahaemolyticus. Int. J. Food Microbiol. 160(3), 245–251 (2013). • Focused on the functions of AphA in V. parahaemolyticus.
- 40 Involvement of LuxS in the regulation of motility and flagella biogenesis in Vibrio alginolyticus. Biosci. Biotech. Bioch. 72(4), 1063–1071 (2008).
- 41 . Dual regulation of genes involved in acetoin biosynthesis and motility/biofilm formation by the virulence activator AphA and the acetate-responsive LysR-type regulator AlsR in Vibrio cholerae. Mol. Microbiol. 57(2), 420–433 (2005).
- 42 . The virulence transcriptional activator AphA enhances biofilm formation by Vibrio cholerae by activating expression of the biofilm regulator VpsT. Infect. Immun. 78(2), 697–703 (2010). •• The regulation mechanism of biofilm formation by AphA in V. cholerae was elucidated.
- 43 . VpsT is a transcriptional regulator required for expression of vps biosynthesis genes and the development of rugose colonial morphology in Vibrio cholerae O1 El Tor. J. Bacteriol. 186(5), 1574–1578 (2004).
- 44 . Regulation of rugosity and biofilm formation in Vibrio cholerae: comparison of VpsT and VpsR regulons and epistasis analysis of vpsT, vpsR, and hapR. J. Bacteriol. 189(2), 388–402 (2007).
- 45 Vibrio cholerae VpsT regulates matrix production and motility by directly sensing cyclic di-GMP. Science. 327(5967), 866–868 (2010).
- 46 . Cellular levels and binding of c-di-GMP control subcellular localization and activity of the Vibrio cholerae transcriptional regulator VpsT. PLoS Pathog. 8(5), e1002719 (2012).
- 47 Transmissibility of cholera: in vivo-formed biofilms and their relationship to infectivity and persistence in the environment. Proc. Natl Acad. Sci. USA 103(16), 6350–6355 (2006).
- 48 . Growth in a biofilm induces a hyperinfectious phenotype in Vibrio cholerae. Infect. Immun. 78(8), 3560–3569 (2010).
- 49 . Adherence to intestinal cells promotes biofilm formation in Vibrio cholerae. J. Infect. Dis. 214(10), 1571–1578 (2016).
- 50 Quorum sensing modulates transcription of cpsQ-mfpABC and mfpABC in Vibrio parahaemolyticus. Int. J. Food. Microbiol. 166(3), 458–463 (2013).
- 51 . Genetic determinants of biofilm development of opaque and translucent Vibrio parahaemolyticus. Mol. Microbiol. 55(4), 1160–1182 (2005).
- 52 . Vibrio cholerae biofilms and cholera pathogenesis. PLoS Neglect. Trop. 10(2), e0004330 (2016).
- 53 . Lysogenic conversion by a filamentous phage encoding cholera toxin. Science 272(5270), 1910–1914 (1996).
- 54 Replication of Vibrio cholerae classical CTX phage. Proc. Natl Acad. Sci. USA 114(9), 2343–2348 (2017).
- 55 . A Vibrio cholerae pathogenicity island associated with epidemic and pandemic strains. Proc. Natl Acad. Sci. USA 95(6), 3134–3139 (1998).
- 56 . Regulation of virulence in Vibrio cholerae: the ToxR regulon. Future Microbiol. 2(3), 335–344 (2007).
- 57 . A Vibrio cholerae LysR homolog, AphB, cooperates with AphA at the tcpPH promoter to activate expression of the ToxR virulence cascade. J. Bacteriol. 181(14), 4250–4256 (1999).
- 58 . A new level in the Vibrio cholerae ToxR virulence cascade: AphA is required for transcriptional activation of the tcpPH operon. Mol. Microbiol. 31(3), 763–771 (1999).
- 59 . Overlapping binding sites for the virulence gene regulators AphA, AphB and cAMP-CRP at the Vibrio cholerae tcpPH promoter. Mol. Microbiol. 41(2), 393–407 (2001).
- 60 . Vibrio parahaemolyticus cell biology and pathogenicity determinants. Microbes. Infect. 13(12–13), 992–1001 (2011).
- 61 . Contribution of Vibrio parahaemolyticus virulence factors to cytotoxicity, enterotoxicity, and lethality in mice. Infect. Immun. 78(4), 1772–1780 (2010).
- 62 . Identification of proteins secreted via Vibrio parahaemolyticus type III secretion system 1. Infect. Immun. 74(2), 1032–1042 (2006).
- 63 . Thermostable direct hemolysin gene of Vibrio parahaemolyticus: a virulence gene acquired by a marine bacterium. Infect. Immun. 63(6), 2093–2099 (1995).
- 64 . Roles of thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH) in Vibrio parahaemolyticus. Front. Microbiol. 5, 805 (2014).
- 65 . Regulation of type III secretion system 1 gene expression in Vibrio parahaemolyticus is dependent on interactions between ExsA, ExsC, and ExsD. Virulence 1(4), 260–272 (2010).
- 66 . Vibrio parahaemolyticus ExsE is requisite for initial adhesion and subsequent type III secretion system 1-dependent autophagy in HeLa cells. Microbiology 158(Pt 9), 2303–2314 (2012).
- 67 . The virulence activator AphA links quorum sensing to pathogenesis and physiology in Vibrio cholerae by repressing the expression of a penicillin amidase gene on the small chromosome. J. Bacteriol. 185(16), 4825–4836 (2003).
- 68 . Carbon regulation and the role in nature of the Escherichia coli penicillin acylase (pac) gene. Mol. Microbiol. 6(15), 2175–2182 (1992).
- 69 . The role of penicillin amidases in nature and in industry. Trends. Biochem. Sci. 16(1), 36–40 (1991).
- 70 Overexpression of penicillin V acylase from Streptomyces lavendulae and elucidation of its catalytic residues. Appl. Environ. Microbiol. 81(4), 1225–1233 (2015).
- 71 . Enzymatic synthesis of beta-lactam antibiotics and N-fatty-acylated amino compounds by the acyl-transfer reaction catalyzed by penicillin V acylase from Streptomyces mobaraensis. Biosci. Biotech. Bioch. 71(6), 1582–1586 (2007).
- 72 . Structural modelling of substrate binding and inhibition in penicillin V acylase from Pectobacterium atrosepticum. Biochem. Biophys. Res. Commun. 437(4), 538–543 (2013).
- 73 . Penicillin V acylases from gram-negative bacteria degrade N-acylhomoserine lactones and attenuate virulence in Pseudomonas aeruginosa. Appl. Microbiol. Biotechnol. 101(6), 2383–2395 (2017).
- 74 . Low cell density regulator AphA upregulates the expression of Vibrio vulnificus iscR gene encoding the Fe-S cluster regulator IscR. J. Microbiol. 52(5), 413–421 (2014).
- 75 . The role of Fe-S proteins in sensing and regulation in bacteria. Curr. Opin. Microbiol. 6(2), 181–185 (2003).
- 76 . What a difference a cluster makes: the multifaceted roles of IscR in gene regulation and DNA recognition. Biochim. Biophys. Acta 1854(9), 1101–1112 (2015).