Cyclic diguanylate signaling proteins control intracellular growth of Legionella pneumophila.
Proteins that metabolize or bind the nucleotide second messenger cyclic diguanylate regulate a wide variety of important processes in bacteria. These processes include motility, biofilm formation, cell division, differentiation, and virulence. The role of cyclic diguanylate signaling in the lifestyle of Legionella pneumophila, the causative agent of Legionnaires' disease, has not previously been examined. The L. pneumophila genome encodes 22 predicted proteins containing domains related to cyclic diguanylate synthesis, hydrolysis, and recognition. We refer to these genes as cdgS (cyclic diguanylate signaling) genes. Strains of L. pneumophila containing deletions of all individual cdgS genes were created and did not exhibit any observable growth defect in growth medium or inside host cells. However, when overexpressed, several cdgS genes strongly decreased the ability of L. pneumophila to grow inside host cells. Expression of these cdgS genes did not affect the Dot/Icm type IVB secretion system, the major determinant of intracellular growth in L. pneumophila. L. pneumophila strains overexpressing these cdgS genes were less cytotoxic to THP-1 macrophages than wild-type L. pneumophila but retained the ability to resist grazing by amoebae. In many cases, the intracellular-growth inhibition caused by cdgS gene overexpression was independent of diguanylate cyclase or phosphodiesterase activities. Expression of the cdgS genes in a Salmonella enterica serovar Enteritidis strain that lacks all diguanylate cyclase activity indicated that several cdgS genes encode potential cyclases. These results indicate that components of the cyclic diguanylate signaling pathway play an important role in regulating the ability of L. pneumophila to grow in host cells.
Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, USA.
Assaf
A
Levi
Marc
M
Folcher
Urs
U
Jenal
Howard A
HA
Shuman
D048248:Acanthamoeba castellanii / Q000382:microbiology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D016952:Legionella pneumophila / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D007877:Legionnaires' Disease / Q000382:microbiology*; D008264:Macrophages / Q000382:microbiology; D015398:Signal Transduction
D001426:Bacterial Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP
Genes Dev. 2009 Jan 1;23(1):93-104
19136627
Annu Rev Microbiol. 2007;61:131-48
17480182
Science. 1998 Feb 6;279(5352):873-6
9452389
Trends Microbiol. 2007 Aug;15(8):372-80
17632005
Trends Microbiol. 1996 Jul;4(7):286-90
8829338
PLoS One. 2009 Jun 23;4(6):e6018
19547710
J Exp Med. 2009 Aug 31;206(9):1899-911
19652017
J Bacteriol. 2006 Dec;188(24):8327-34
17028282
Infect Immun. 1995 Jul;63(7):2499-507
7790062
Proc Natl Acad Sci U S A. 1998 May 26;95(11):5857-64
9600884
Mol Microbiol. 2007 Aug;65(4):876-95
17645452
Cell. 2006 Mar 10;124(5):1025-37
16530048
J Bacteriol. 2008 Jan;190(2):463-75
17993515
PLoS Pathog. 2008 Aug 01;4(8):e1000117
18670632
Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1669-74
9465074
J Biol Chem. 2006 Oct 20;281(42):32015-24
16923812
Science. 2004 Feb 27;303(5662):1358-61
14988561
J Clin Invest. 1980 Sep;66(3):441-50
7190579
Semin Respir Infect. 1989 Mar;4(1):32-9
2652233
Mol Microbiol. 1993 Jan;7(1):7-19
8382332
Bioinformatics. 2006 Jan 1;22(1):3-6
16249258
J Bacteriol. 2007 May;189(9):3613-23
17322315
Mol Microbiol. 2010 Aug;77(4):930-42
20572940
Nature. 2009 Jun 18;459(7249):1015-8
19536266
Structure. 2007 Aug;15(8):915-27
17697997
FEMS Microbiol Rev. 2002 Jun;26(2):149-62
12069880
Annu Rev Cell Dev Biol. 2010;26:261-83
20929312
J Bacteriol. 2009 Apr;191(8):2461-73
19218380
Nat Rev Microbiol. 2009 Oct;7(10):724-35
19756011
J Biol Chem. 2006 Oct 13;281(41):30310-4
16920715
Science. 2010 Aug 13;329(5993):845-848
20705859
Mol Microbiol. 2004 Aug;53(4):1123-34
15306016
J Bacteriol. 2004 Nov;186(21):7221-8
15489433
Nat Rev Microbiol. 2009 Jan;7(1):13-24
19011659
Mol Microbiol. 2008 Jul;69(2):376-89
18485075
J Bacteriol. 2010 Sep;192(17):4504-16
20622069
J Bacteriol. 2004 Jun;186(12):3814-25
15175295
Cell. 2010 Apr 2;141(1):107-16
20303158
Mol Microbiol. 2006 Nov;62(4):1014-34
17010156
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17084-9
15569936
EMBO J. 2007 Dec 12;26(24):5153-66
18034161
Mol Microbiol. 1998 Jan;27(2):323-36
9484888
Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9607-11
1409673
J Bacteriol. 2008 Aug;190(15):5178-89
18502872
Mol Microbiol. 1999 Apr;32(2):379-91
10231493
Infect Immun. 2005 Sep;73(9):5873-82
16113306
J Bacteriol. 2006 Dec;188(23):8196-205
16980460
J Bacteriol. 2008 Feb;190(3):851-60
17993539
Mol Microbiol. 2009 Jun;72(6):1500-16
19460094
Infect Immun. 1997 Dec;65(12):5057-66
9393796
Infect Immun. 1998 Sep;66(9):4450-60
9712800
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7997-8002
19416883
Cell Microbiol. 2009 Oct;11(10):1435-43
19563462
Genes Dev. 2006 Sep 15;20(18):2605-17
16980588
J Mol Biol. 2010 Apr 23;398(1):97-110
20226196
Mol Microbiol. 2005 Jun;56(5):1234-45
15882417
Mol Microbiol. 2010 Jun 1;76(5):1295-305
20444091
Science. 2008 Jul 18;321(5887):411-3
18635805
Mol Cell. 2010 Apr 9;38(1):128-39
20346719
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4112-7
17360486
Nat Rev Microbiol. 2009 Apr;7(4):263-73
19287449
J Bacteriol. 1999 Aug;181(16):4879-89
10438758
Mol Microbiol. 2007 Sep;65(6):1474-84
17824927
Science. 2010 Feb 12;327(5967):866-8
20150502
Mol Microbiol. 2004 Aug;53(3):857-69
15255898
Trends Microbiol. 1998 Jul;6(7):253-5
9717210
Curr Opin Microbiol. 2006 Apr;9(2):218-28
16530465
Annu Rev Genet. 2006;40:385-407
16895465
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2839-44
16477007