Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection.
Chronic infections are an increasing problem due to the aging population and the increase in antibiotic resistant organisms. Therefore, understanding the host-pathogen interactions that result in chronic infection is of great importance. Here, we investigate the molecular basis of chronic bacterial cystitis. We establish that introduction of uropathogenic E. coli (UPEC) into the bladders of C3H mice results in two distinct disease outcomes: resolution of acute infection or development of chronic cystitis lasting months. The incidence of chronic cystitis is both host strain and infectious dose-dependent. Further, development of chronic cystitis is preceded by biomarkers of local and systemic acute inflammation at 24 hours post-infection, including severe pyuria and bladder inflammation with mucosal injury, and a distinct serum cytokine signature consisting of elevated IL-5, IL-6, G-CSF, and the IL-8 analog KC. Mice deficient in TLR4 signaling or lymphocytes lack these innate responses and are resistant, to varying degrees, to developing chronic cystitis. Treatment of C3H mice with the glucocorticoid anti-inflammatory drug dexamethasone prior to UPEC infection also suppresses the development of chronic cystitis. Finally, individuals with a history of chronic cystitis, lasting at least 14 days, are significantly more susceptible to redeveloping severe, chronic cystitis upon bacterial challenge. Thus, we have discovered that the development of chronic cystitis in C3H mice by UPEC is facilitated by severe acute inflammatory responses early in infection, which subsequently are predisposing to recurrent cystitis, an insidious problem in women. Overall, these results have significant implications for our understanding of how early host-pathogen interactions at the mucosal surface determines the fate of disease.
Hannan
Thomas J
TJ
Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, Missouri, USA.
Mysorekar
Indira U
IU
Hung
Chia S
CS
Isaacson-Schmid
Megan L
ML
Hultgren
Scott J
SJ
D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014552:Urinary Tract Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology*
D016207:Cytokines
J Biol Chem. 2009 Jan 2;284(1):446-454
18996840
J Biol Chem. 2002 Mar 1;277(9):7412-9
11744708
Infect Immun. 1995 Oct;63(10):4138-42
7558330
Cell Host Microbe. 2007 Jun 14;1(4):287-98
17710226
Infect Immun. 2008 Jul;76(7):3337-45
18411285
Infect Immun. 2001 Jul;69(7):4572-9
11402001
Infect Immun. 1989 Nov;57(11):3383-8
2680971
Am J Med. 2002 Jul 8;113 Suppl 1A:14S-19S
12113867
Infect Immun. 1993 Apr;61(4):1307-14
8454332
Microbiology (Reading). 2007 Jun;153(Pt 6):1711-1719
17526829
Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22439-44
20018753
N Engl J Med. 2009 Jan 29;360(5):439-43
19179312
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1333-8
14739341
J Immunol. 1987 May 15;138(10):3475-80
3553327
Expert Opin Pharmacother. 2009 Nov;10(16):2609-23
19827989
Immunol Lett. 2004 Feb 15;91(2-3):103-11
15019277
Infection. 1984 Mar-Apr;12(2):118-23
6376364
Blood. 2008 Jan 1;111(1):42-9
17928531
Postgrad Med J. 1972 Feb;48(556):69-75
4552445
J Immunol. 2010 Feb 15;184(4):2065-75
20083670
J Infect Dis. 2000 Oct;182(4):1177-82
10979915
EMBO J. 2000 Jun 15;19(12):2803-12
10856226
J Urol. 2005 Jan;173(1):21-6
15592018
J Immunol. 2001 Jan 15;166(2):1148-55
11145696
Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14966-71
19706440
J Infect Dis. 2000 Feb;181(2):774-8
10669375
Infect Immun. 1998 Jun;66(6):2798-802
9596750
Clin Infect Dis. 2002 May 1;34(9):1165-9
11941541
J Leukoc Biol. 2008 Jan;83(1):64-70
17884993
Cell Microbiol. 2008 Dec;10(12):2568-78
18754853
Infect Immun. 2002 Dec;70(12):7042-9
12438384
J Clin Pathol. 1974 Apr;27(4):297-307
4855039
J Infect Dis. 2007 Apr 15;195(8):1227-34
17357062
PLoS One. 2009 Jun 22;4(6):e5990
19543401
J Urol. 1990 Feb;143(2):330-2
2405189
PLoS Pathog. 2009 May;5(5):e1000448
19478872
Infect Immun. 2005 Nov;73(11):7657-68
16239570
J Immunol. 2000 Nov 1;165(9):5287-94
11046063
Nat Med. 2008 Jun;14(6):633-40
18488036
J Infect Dis. 1999 Oct;180(4):1220-9
10479151
Curr Opin Microbiol. 2006 Feb;9(1):33-9
16406777
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4203-8
12655047
N Engl J Med. 2005 Oct 20;353(16):1711-23
16236742
J Leukoc Biol. 2002 Dec;72(6):1122-32
12488493
J Exp Med. 1974 Nov 1;140(5):1147-61
4138849
Cell Microbiol. 2002 Jan;4(1):19-28
11856170
Leukemia. 2001 Aug;15(8):1248-55
11480567
Blood. 1998 Apr 1;91(7):2525-35
9516154
Scand J Infect Dis. 2004;36(4):296-301
15198188
Curr Opin Immunol. 2008 Jun;20(3):288-94
18511250
Am J Med. 2002 Jul 8;113 Suppl 1A:5S-13S
12113866
Nat Med. 2007 May;13(5):625-30
17417648
Am J Med Genet. 1999 Apr 23;83(5):422-4
10232756
Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14170-5
16968784
Genes Immun. 2006 Mar;7(2):122-9
16395389
J Immunol. 2006 Mar 1;176(5):3080-6
16493067
J Infect Dis. 2009 Feb 1;199(3):355-61
19061424
Science. 1998 Nov 20;282(5393):1494-7
9822381
J Urol. 1999 Jan;161(1):338-41
10037434
J Biol Chem. 2004 Apr 30;279(18):18944-51
14976212
Infect Immun. 2002 Aug;70(8):4501-9
12117962
Cell Microbiol. 2006 Apr;8(4):704-17
16548895
Infect Immun. 1981 Sep;33(3):933-8
6116675
PLoS Med. 2007 Dec;4(12):e329
18092884
Kansenshogaku Zasshi. 1994 Dec;68(12):1498-511
7876672
Science. 2003 Jul 4;301(5629):105-7
12843396
Infect Immun. 2003 Nov;71(11):6653-7
14573691
J Infect Dis. 2007 Aug 1;196(3):475-84
17597463
Emerg Infect Dis. 1998 Jul-Sep;4(3):475-87
9716980
Ann Intern Med. 2001 Jul 3;135(1):41-50
11434731
Cell Microbiol. 2007 Sep;9(9):2230-41
17490405
Nat Rev Microbiol. 2004 Sep;2(9):747-65
15372085
PLoS Pathog. 2007 Apr;3(4):e60
17465679
Infect Immun. 2007 Jan;75(1):52-60
17074856
J Urol. 2007 Apr;177(4):1349-53; quiz 1591
17382730
Nat Med. 2003 Oct;9(10):1318-22
12949501
Infect Immun. 1996 Apr;64(4):1369-72
8606102
Cytokine. 1996 Sep;8(9):686-97
8932979
Infect Immun. 1991 Jan;59(1):421-7
1987054
Ann N Y Acad Sci. 2002 Jun;963:332-5
12095961