TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder.
The remarkable resistance of the urinary tract to infection has been attributed to its physical properties and the innate immune responses triggered by pattern recognition receptors lining the tract. We report a distinct TLR4 mediated mechanism in bladder epithelial cells (BECs) that abrogates bacterial invasion, a necessary step for successful infection. Compared to controls, uropathogenic type 1 fimbriated Escherichia coli and Klebsiella pneumoniae invaded BECs of TLR4 mutant mice in 10-fold or greater numbers. TLR4 mediated suppression of bacterial invasion was linked to increased intracellular cAMP levels which negatively impacted Rac-1 mediated mobilization of the cytoskeleton. Artificially increasing intracellular cAMP levels in BECs of TLR4 mutant mice restored resistance to type 1 fimbriated bacterial invasion. This finding reveals a novel function for TLR4 and another facet of bladder innate defense.
Song
Jeongmin
J
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Bishop
Brian L
BL
Li
Guojie
G
Duncan
Matthew J
MJ
Abraham
Soman N
SN
D000818:Animals; D001424:Bacterial Infections / Q000517:prevention & control*; D000242:Cyclic AMP / Q000502:physiology*; D004926:Escherichia coli / Q000472:pathogenicity; D016905:Gram-Negative Bacterial Infections / Q000517:prevention & control; D006801:Humans; D007711:Klebsiella pneumoniae / Q000472:pathogenicity; D051379:Mice; D008809:Mice, Inbred C3H; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D001743:Urinary Bladder / Q000382:microbiology* / Q000502:physiology*; D001745:Urinary Bladder Diseases / Q000517:prevention & control*; D014552:Urinary Tract Infections / Q000517:prevention & control*; D019459:Urothelium / Q000382:microbiology
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000242:Cyclic AMP
Mol Interv. 2002 Jun;2(3):168-84
14993377
J Neurosci Res. 2004 Mar 15;75(6):733-41
14994334
J Biol Chem. 2004 Apr 30;279(18):18944-51
14976212
Science. 2004 May 14;304(5673):1014-8
15143282
Infect Immun. 2004 Jun;72(6):3179-86
15155619
Biochim Biophys Acta. 2004 Jul 5;1692(2-3):159-74
15246685
Annu Rev Biochem. 1976;45:501-30
786156
Infect Immun. 1981 Feb;31(2):564-70
7012012
Infect Immun. 1983 Apr;40(1):265-72
6131870
J Bacteriol. 1984 Oct;160(1):61-6
6148338
Infect Immun. 1984 Dec;46(3):839-44
6389367
Infect Immun. 1985 Jun;48(3):625-8
2860067
J Bacteriol. 1986 Mar;165(3):1033-6
2419305
J Immunol. 1987 May 15;138(10):3475-80
3553327
Rev Infect Dis. 1987 May-Jun;9(3):470-87
2885910
Nature. 1988 Dec 15;336(6200):682-4
2904657
Nature. 1994 Jan 6;367(6458):40-6
8107774
J Biol Chem. 1997 Apr 18;272(16):10353-60
9099672
Science. 1997 Apr 25;276(5312):607-11
9110982
J Clin Invest. 1997 Sep 1;100(5):1123-36
9276729
Biochem Pharmacol. 1998 Nov 1;56(9):1229-36
9802335
J Cell Biol. 1998 Nov 30;143(5):1385-98
9832565
Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2427-33
15271660
Microbes Infect. 2004 Dec;6(15):1368-73
15596122
Biochem J. 2005 Feb 1;385(Pt 3):737-44
15377280
Eur J Clin Invest. 2005 Apr;35(4):227-35
15816991
Arthritis Rheum. 2005 Apr;52(4):1297-304
15818670
Respir Res. 2005;6:51
15935092
J Immunol. 2005 Oct 1;175(7):4490-8
16177092
Curr Opin Microbiol. 2006 Feb;9(1):33-9
16406777
Eur J Immunol. 2006 Feb;36(2):267-77
16385628
Am J Physiol Lung Cell Mol Physiol. 2006 Apr;290(4):L730-L737
16299055
Cell Death Differ. 2006 May;13(5):816-25
16410796
Nat Immunol. 2006 Oct;7(10):1029-35
16985500
PLoS Pathog. 2007 Apr;3(4):e60
17465679
Nat Med. 2007 May;13(5):625-30
17417648
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8829-35
10922042
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13766-71
11095740
J Immunol. 2001 Jan 15;166(2):1148-55
11145696
Cell Microbiol. 2001 Mar;3(3):153-8
11260138
J Biol Chem. 2001 Dec 21;276(51):47895-900
11606581
Cell Microbiol. 2002 Jan;4(1):19-28
11856170
Mol Biol Cell. 2002 Mar;13(3):830-46
11907265
J Recept Signal Transduct Res. 2002 Feb-Nov;22(1-4):79-110
12503609
Infect Immun. 2003 Mar;71(3):1470-80
12595465
Cell Mol Neurobiol. 2003 Jun;23(3):305-14
12825829
Traffic. 2004 Mar;5(3):117-28
15086788