Evidence for Direct Control of Virulence and Defense Gene Circuits by the Pseudomonas aeruginosa Quorum Sensing Regulator, MvfR.
Pseudomonas aeruginosa defies eradication by antibiotics and is responsible for acute and chronic human infections due to a wide variety of virulence factors. Currently, it is believed that MvfR (PqsR) controls the expression of many of these factors indirectly via the pqs and phnAB operons. Here we provide strong evidence that MvfR may also bind and directly regulate the expression of additional 35 loci across the P. aeruginosa genome, including major regulators and virulence factors, such as the quorum sensing (QS) regulators lasR and rhlR, and genes involved in protein secretion, translation, and response to oxidative stress. We show that these anti-oxidant systems, AhpC-F, AhpB-TrxB2 and Dps, are critical for P. aeruginosa survival to reactive oxygen species and antibiotic tolerance. Considering that MvfR regulated compounds generate reactive oxygen species, this indicates a tightly regulated QS self-defense anti-poisoning system. These findings also challenge the current hierarchical regulation model of P. aeruginosa QS systems by revealing new interconnections between them that suggest a circular model. Moreover, they uncover a novel role for MvfR in self-defense that favors antibiotic tolerance and cell survival, further demonstrating MvfR as a highly desirable anti-virulence target.
Department of Surgery, Massachusetts General Hospital, Boston MA 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston MA 02115, USA.|Shriners Hospitals for Children Boston, Boston, 02114, Massachusetts, USA.
Damien
D
Maura
Department of Surgery, Massachusetts General Hospital, Boston MA 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston MA 02115, USA.|Shriners Hospitals for Children Boston, Boston, 02114, Massachusetts, USA.|Institute of Dental Sciences and School of Dental Medicine, Hebrew University, Jerusalem P.O.B 12272, 91120, Israel.
Ronen
R
Hazan
Department of Surgery, Massachusetts General Hospital, Boston MA 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston MA 02115, USA.|Shriners Hospitals for Children Boston, Boston, 02114, Massachusetts, USA.
Tomoe
T
Kitao
Department of Surgery, Massachusetts General Hospital, Boston MA 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston MA 02115, USA.|Shriners Hospitals for Children Boston, Boston, 02114, Massachusetts, USA.
Alicia E
AE
Ballok
Department of Surgery, Massachusetts General Hospital, Boston MA 02114, USA.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston MA 02115, USA.|Shriners Hospitals for Children Boston, Boston, 02114, Massachusetts, USA.
Laurence G
LG
Rahme
Arch Biochem Biophys. 2005 Jan 1;433(1):240-54
15581580
Nat Biotechnol. 2008 Dec;26(12):1351-9
19029915
Bioinformatics. 2015 Jan 15;31(2):166-9
25260700
J Biol Chem. 2010 Jul 16;285(29):22689-95
20479007
BMC Microbiol. 2006 Jun 12;6:53
16768798
Pathog Dis. 2013 Apr;67(3):159-73
23620179
Philos Trans R Soc Lond B Biol Sci. 2012 Apr 19;367(1592):1059-72
22411978
Biochim Biophys Acta. 1977 Jan 6;459(1):119-27
831781
Environ Microbiol. 2014 Aug;16(8):2568-90
24571640
Trends Microbiol. 2005 Dec;13(12):581-8
16216510
J Bacteriol. 1980 Jan;141(1):156-63
6243619
Bioinformatics. 2010 Jan 1;26(1):139-40
19910308
Clin Microbiol Rev. 2009 Oct;22(4):582-610
19822890
Mol Microbiol. 2015 Jan;95(2):352-64
25425348
Annu Rev Pharmacol Toxicol. 2015;55:313-32
25251995
Infect Immun. 1992 Feb;60(2):328-36
1730464
J Bacteriol. 2013 May;195(9):2011-20
23457248
Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18947-52
19028873
J Bacteriol. 2005 Jul;187(13):4372-80
15968046
Nature. 2005 Sep 15;437(7057):422-5
16163359
Appl Microbiol Biotechnol. 2010 May;86(6):1637-45
20352420
Science. 1993 May 21;260(5111):1127-30
8493556
Nat Rev Microbiol. 2014 Feb;12(2):137-48
24384601
Antimicrob Agents Chemother. 1981 Dec;20(6):814-20
6798928
Biochim Biophys Acta. 2010 Aug;1800(8):798-805
20138126
Proc Natl Acad Sci U S A. 2007 May 8;104(19):7969-74
17470804
J Bacteriol. 2002 Dec;184(23):6472-80
12426334
J Ind Microbiol Biotechnol. 2010 Jul;37(7):643-72
20446033
Korean J Intern Med. 2012 Jun;27(2):128-42
22707882
Mol Microbiol. 1995 Jul;17(2):333-43
7494482
Free Radic Biol Med. 2014 Jan;66:75-87
23899494
ISME J. 2011 Aug;5(8):1332-43
21368905
J Am Soc Mass Spectrom. 2004 Jun;15(6):862-9
15144975
PLoS Pathog. 2011 Aug;7(8):e1002192
21829370
Mol Microbiol. 2006 Dec;62(6):1689-99
17083468
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1339-44
14739337
ACS Chem Biol. 2012 Sep 21;7(9):1496-501
22765028
Curr Biol. 2016 Jan 25;26(2):195-206
26776731
PLoS Pathog. 2012;8(11):e1003024
23166496
Mol Microbiol. 2009 Sep;73(6):1072-85
19682264
J Appl Microbiol. 2011 Feb;110(2):375-86
21143355
Science. 1995 Jun 30;268(5219):1899-902
7604262
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11229-34
10500159
Antimicrob Agents Chemother. 2006 Mar;50(3):949-54
16495256
J Bacteriol. 1997 May;179(10):3127-32
9150205
J Antimicrob Chemother. 1992 Nov;30(5):615-23
1493979
PLoS Pathog. 2007 Sep 14;3(9):1229-39
17941706
J Bacteriol. 2000 May;182(10):2702-8
10781536
Microbiology. 2009 Mar;155(Pt 3):712-23
19246742
Microbiology. 2008 Dec;154(Pt 12):3609-23
19047729
Mol Microbiol. 2005 Feb;55(4):998-1014
15686549
Front Cell Infect Microbiol. 2013 Oct 02;3:59
24106689
J Bacteriol. 2008 Nov;190(21):7043-51
18776012
Science. 1988 Apr 29;240(4852):640-2
2834821
FEMS Microbiol Rev. 2006 Mar;30(2):274-91
16472307
PLoS Pathog. 2008 Sep 26;4(9):e1000166
18818733
Nat Rev Microbiol. 2007 Jan;5(1):48-56
17143318
PLoS Pathog. 2014 Aug 21;10(8):e1004321
25144274
J Bacteriol. 1994 Apr;176(7):2044-54
8144472
Annu Rev Microbiol. 2010;64:357-72
20528688
Nucleic Acids Res. 2008 Jul;36(12):3950-5
18515344
J Am Chem Soc. 2012 Oct 3;134(39):16143-6
22992202
Chem Biol. 2012 Mar 23;19(3):381-90
22444593
J Bacteriol. 1991 May;173(9):3000-9
1902216
FEMS Microbiol Rev. 2011 Mar;35(2):247-74
20738404
Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14613-8
11724939
Trends Mol Med. 2004 Dec;10(12):599-606
15567330
Antioxid Redox Signal. 2014 Feb 20;20(6):1000-37
23992156
Microbiology. 2006 Jun;152(Pt 6):1679-86
16735731
Nat Biotechnol. 2011 Jan;29(1):24-6
21221095
Biometals. 2009 Feb;22(1):15-22
19130263
Proc Int Conf Intell Syst Mol Biol. 1994;2:28-36
7584402
Int J Med Microbiol. 2006 Apr;296(2-3):73-81
16476569
Biol Chem. 2007 Aug;388(8):839-45
17655503
J Med Microbiol. 2003 May;52(Pt 5):403-8
12721316
J Hosp Infect. 2009 Dec;73(4):338-44
19699552
PLoS Pathog. 2013;9(7):e1003508
23935486
Nat Chem Biol. 2012 Mar 18;8(5):431-3
22426114
J Bacteriol. 1995 Dec;177(24):7155-63
8522523
Mol Microbiol. 2011 May;80(4):868-85
21375594
FEMS Microbiol Lett. 2004 Jan 15;230(1):27-34
14734162
PLoS Pathog. 2010 Mar 12;6(3):e1000810
20300606
PLoS One. 2013 Dec 19;8(12):e80140
24367477
Mol Microbiol. 2007 Feb;63(4):937-40
17238916
Subcell Biochem. 2007;44:143-93
18084893
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Jun 1;68(Pt 6):695-7
22684073
Bioinformatics. 2009 Jul 15;25(14):1754-60
19451168
Genome Biol. 2007;8(2):R24
17324271
Curr Opin Microbiol. 2009 Apr;12(2):182-91
19249239
Front Microbiol. 2015 Sep 30;6:1003
26483762
Int J Antimicrob Agents. 2011 Mar;37(3):261-5
21295952
Int J Mol Sci. 2011 Jan 13;12(1):334-52
21339989
Bioresour Technol. 2011 Jun;102(11):6377-84
21498076
Appl Microbiol Biotechnol. 2010 May;86(5):1323-36
20336292
J Bacteriol. 2000 Aug;182(16):4533-44
10913087
BMC Pulm Med. 2010 Nov 07;10:56
21054900
EMBO Rep. 2015 Nov;16(11):1482-500
26474900
Nucleic Acids Res. 2012 May;40(10):4320-33
22275523
BMC Microbiol. 2012 Nov 13;12:259
23148795