Quorum sensing and virulence of Pseudomonas aeruginosa during lung infection of cystic fibrosis patients.
Pseudomonas aeruginosa is the predominant microorganism in chronic lung infection of cystic fibrosis patients. The chronic lung infection is preceded by intermittent colonization. When the chronic infection becomes established, it is well accepted that the isolated strains differ phenotypically from the intermittent strains. Dominating changes are the switch to mucoidity (alginate overproduction) and loss of epigenetic regulation of virulence such as the Quorum Sensing (QS). To elucidate the dynamics of P. aeruginosa QS systems during long term infection of the CF lung, we have investigated 238 isolates obtained from 152 CF patients at different stages of infection ranging from intermittent to late chronic. Isolates were characterized with regard to QS signal molecules, alginate, rhamnolipid and elastase production and mutant frequency. The genetic basis for change in QS regulation were investigated and identified by sequence analysis of lasR, rhlR, lasI and rhlI. The first QS system to be lost was the one encoded by las system 12 years (median value) after the onset of the lung infection with subsequent loss of the rhl encoded system after 17 years (median value) shown as deficiencies in production of the 3-oxo-C12-HSL and C4-HSL QS signal molecules respectively. The concomitant development of QS malfunction significantly correlated with the reduced production of rhamnolipids and elastase and with the occurrence of mutations in the regulatory genes lasR and rhlR. Accumulation of mutations in both lasR and rhlR correlated with development of hypermutability. Interestingly, a higher number of mucoid isolates were found to produce C4-HSL signal molecules and rhamnolipids compared to the non-mucoid isolates. As seen from the present data, we can conclude that P. aeruginosa and particularly the mucoid strains do not lose the QS regulation or the ability to produce rhamnolipids until the late stage of the chronic infection.
Bjarnsholt
Thomas
T
Institute for International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Jensen
Peter Østrup
PØ
Jakobsen
Tim Holm
TH
Phipps
Richard
R
Nielsen
Anne Kirstine
AK
Rybtke
Morten Theil
MT
Tolker-Nielsen
Tim
T
Givskov
Michael
M
Høiby
Niels
N
Ciofu
Oana
O
D003550:Cystic Fibrosis / Q000150:complications*; D005798:Genes, Bacterial; D006017:Glycolipids / Q000032:analysis; D006801:Humans; D008171:Lung Diseases / Q000382:microbiology*; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D053038:Quorum Sensing / Q000235:genetics*; D013997:Time Factors; D014774:Virulence / Q000235:genetics
D006017:Glycolipids; C418382:rhamnolipid
Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11115-9
1763027
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15876-81
17898171
J Med Microbiol. 2003 Sep;52(Pt 9):731-740
12909647
J Bacteriol. 1997 May;179(10):3127-32
9150205
Microbiology (Reading). 2009 Mar;155(Pt 3):712-723
19246742
J Clin Microbiol. 2005 Oct;43(10):5247-55
16207991
Gene. 1995 Dec 1;166(1):175-6
8529885
J Bacteriol. 1995 Feb;177(3):815-7
7836318
Int J Med Microbiol. 2006 Apr;296(2-3):93-102
16503417
J Bacteriol. 1992 Jun;174(12):4064-9
1597420
J Cyst Fibros. 2005 Aug;4 Suppl 2:49-54
16023416
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8487-92
16687478
Philos Trans R Soc Lond B Biol Sci. 2000 May 29;355(1397):667-80
10874739
Microbiology (Reading). 2009 Nov;155(Pt 11):3500-3508
19643762
J Bacteriol. 1980 Jun;142(3):836-42
6769912
Mol Microbiol. 2003 Oct;50(1):29-43
14507361
Infect Immun. 2007 May;75(5):2214-24
17261614
Scand J Respir Dis. 1977 Apr;58(2):65-79
404701
Microbiology (Reading). 2007 May;153(Pt 5):1329-1338
17464047
J Clin Microbiol. 1992 Jul;30(7):1848-55
1378455
Infect Immun. 1984 Jan;43(1):161-5
6317565
J Bacteriol. 1994 May;176(10):2781-7
8188580
J Biol Chem. 2007 May 4;282(18):13592-600
17363368
J Bacteriol. 2006 May;188(9):3365-70
16621831
Eur Respir J. 2008 Apr;31(4):822-9
18094014
Microbiology (Reading). 2007 Jan;153(Pt 1):225-37
17185551
J Mol Biol. 2010 Mar 5;396(4):849-57
20064524
Infect Immun. 1990 Oct;58(10):3363-8
2401567
J Clin Microbiol. 2000 Jan;38(1):464-5
10618146
Microbiology (Reading). 1999 Jun;145 ( Pt 6):1349-1357
10411261
Antimicrob Agents Chemother. 2008 Oct;52(10):3648-63
18644954
APMIS. 2009 Feb;117(2):95-107
19239431
Antimicrob Agents Chemother. 2009 Jun;53(6):2483-91
19332676
Microbes Infect. 2000 Nov;2(14):1721-31
11137045
APMIS. 2009 Jul;117(7):537-46
19594494
Mol Microbiol. 2007 Apr;64(2):512-33
17493132
Infect Immun. 2005 Apr;73(4):2504-14
15784597
Science. 2000 May 19;288(5469):1251-4
10818002
Pediatr Pulmonol. 2009 Jun;44(6):547-58
19418571
Thorax. 1992 Jan;47(1):6-13
1539148
Infect Immun. 2009 Dec;77(12):5631-9
19805523
FEMS Microbiol Lett. 2000 Mar 15;184(2):273-8
10713433
Microbiology (Reading). 2002 Jan;148(Pt 1):87-102
11782502
Emerg Infect Dis. 1998 Oct-Dec;4(4):551-60
9866731
Microbiol Rev. 1996 Sep;60(3):539-74
8840786
Antimicrob Agents Chemother. 2005 Jun;49(6):2276-82
15917521
J Bacteriol. 2002 Sep;184(17):4912-9
12169617
J Clin Microbiol. 1995 Sep;33(9):2233-9
7494007
Thorax. 2010 Jan;65(1):57-62
19846469
Nature. 2007 Nov 15;450(7168):411-4
18004383
APMIS. 1991 Jun;99(6):492-8
1905144