Early Severe Inflammatory Responses to Uropathogenic Predispose to Chronic and Recurrent Urinary Tract Infection

English version České info

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.

Vyšlo v časopise: Early Severe Inflammatory Responses to Uropathogenic Predispose to Chronic and Recurrent Urinary Tract Infection. PLoS Pathog 6(8): e32767. doi:10.1371/journal.ppat.1001042
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001042

Souhrn

Zdroje

1. AriasCa

MurrayBe

2009 Antibiotic-Resistant Bugs In The 21st Century–A Clinical Super-Challenge. N Engl J Med 360 439 443

2. KimEy

BattaileJt

PatelAc

YouY

AgapovE

2008 Persistent Activation Of An Innate Immune Response Translates Respiratory Viral Infection Into Chronic Lung Disease. Nat Med 14 633 640

3. CassellGh

1998 Infectious Causes Of Chronic Inflammatory Diseases And Cancer. Emerg Infect Dis 4 475 487

4. MonackDm

MuellerA

FalkowS

2004 Persistent Bacterial Infections: The Interface Of The Pathogen And The Host Immune System. Nat Rev Microbiol 2 747 765

5. NickelJc

2005 Management Of Urinary Tract Infections: Historical Perspective And Current Strategies: Part 1–Before Antibiotics. J Urol 173 21 26

6. GrieblingTl

2007 Urinary Tract Infection In Women.

LitwinMs

SaigalCs

Urologic Diseases In America Us Dhhs, Phs, Nih, Niddk Washington, Dc Us Gpo 587 620

7. FoxmanB

2002 Epidemiology Of Urinary Tract Infections: Incidence, Morbidity, And Economic Costs. American Journal Of Medicine 113 Suppl 1a 5s 13s

8. LangermannS

MollbyR

BurleinJe

PalaszynskiSr

AugusteCg

2000 Vaccination With Fimh Adhesin Protects Cynomolgus Monkeys From Colonization And Infection By Uropathogenic Escherichia Coli. J Infect Dis 181 774 778

9. ThumbikatP

WaltenbaughC

SchaefferAj

KlumppDj

2006 Antigen-Specific Responses Accelerate Bacterial Clearance In The Bladder. J Immunol 176 3080 3086

10. HopkinsWj

ElkahwajiJ

BeierleLm

LeversonGe

UehlingDt

2007 Vaginal Mucosal Vaccine For Recurrent Urinary Tract Infections In Women: Results Of A Phase 2 Clinical Trial. J Urol 177 1349 1353 Quiz 1591

11. HopkinsWj

UehlingDt

WargowskiDs

1999 Evaluation Of A Familial Predisposition To Recurrent Urinary Tract Infections In Women. Am J Med Genet 83 422 424

12. ScholesD

HootonTm

RobertsPl

StapletonAe

GuptaK

2000 Risk Factors For Recurrent Urinary Tract Infection In Young Women. J Infect Dis 182 1177 1182

13. GuptaK

HootonTm

StammWe

2001 Increasing Antimicrobial Resistance And The Management Of Uncomplicated Community-Acquired Urinary Tract Infections. Ann Intern Med 135 41 50

14. RazR

ChazanB

KennesY

ColodnerR

RottensterichE

2002 Empiric Use Of Trimethoprim-Sulfamethoxazole (Tmp-Smx) In The Treatment Of Women With Uncomplicated Urinary Tract Infections, In A Geographical Area With A High Prevalence Of Tmp-Smx-Resistant Uropathogens. Clin Infect Dis 34 1165 1169

15. RonaldA

2002 The Etiology Of Urinary Tract Infection: Traditional And Emerging Pathogens. American Journal Of Medicine 113 Suppl 1a 14s 19s

16. MartinezJj

MulveyMa

SchillingJd

PinknerJs

HultgrenSj

2000 Type 1 Pilus-Mediated Bacterial Invasion Of Bladder Epithelial Cells. Embo Journal 19 2803 2812

17. MulveyMa

Lopez-BoadoYs

WilsonCl

RothR

ParksWc

1998 Induction And Evasion Of Host Defenses By Type 1-Piliated Uropathogenic Escherichia Coli. Science 282 1494 1497

18. DuncanMj

LiG

ShinJs

CarsonJl

AbrahamSn

2004 Bacterial Penetration Of Bladder Epithelium Through Lipid Rafts. Journal Of Biological Chemistry 279 18944 18951

19. MartinezJj

HultgrenSj

2002 Requirement Of Rho-Family Gtpases In The Invasion Of Type 1-Piliated Uropathogenic Escherichia Coli. Cellular Microbiology 4 19 28

20. SongJ

BishopBl

LiG

DuncanMj

AbrahamSn

2007 Tlr4-Initiated And Camp-Mediated Abrogation Of Bacterial Invasion Of The Bladder. Cell Host Microbe 1 287 298

21. DhakalBk

MulveyMa

2009 Uropathogenic Escherichia Coli Invades Host Cells Via An Hdac6-Modulated Microtubule-Dependent Pathway. J Biol Chem 284 446 454

22. BishopBl

DuncanMj

SongJ

LiG

ZaasD

2007 Cyclic Amp-Regulated Exocytosis Of Escherichia Coli From Infected Bladder Epithelial Cells. Nat Med 13 625 630

23. AndersonGg

PalermoJj

SchillingJd

RothR

HeuserJ

2003 Intracellular Bacterial Biofilm-Like Pods In Urinary Tract Infections. Science 301 105 107

24. WrightKj

SeedPc

HultgrenSj

2007 Development Of Intracellular Bacterial Communities Of Uropathogenic Escherichia Coli Depends On Type 1 Pili. Cell Microbiol 9 2230 2241

25. JusticeSs

HungC

TheriotJa

FletcherDa

AndersonGg

2004 Differentiation And Developmental Pathways Of Uropathogenic Escherichia Coli In Urinary Tract Pathogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 101 1333 1338

26. ChenSl

HungCs

PinknerJs

WalkerJn

CusumanoCk

2009 Positive Selection Identifies An In Vivo Role For Fimh During Urinary Tract Infection In Addition To Mannose Binding. Proc Natl Acad Sci U S A 106 22439 22444

27. GarofaloCk

HootonTm

MartinSm

StammWe

PalermoJj

2007 Escherichia Coli From Urine Of Female Patients With Urinary Tract Infections Is Competent For Intracellular Bacterial Community Formation. Infection And Immunity 75 52 60

28. RosenDa

HootonTm

StammWe

HumphreyPa

HultgrenSj

2007 Detection Of Intracellular Bacterial Communities In Human Urinary Tract Infection. Plos Med 4 E329

29. RosenDa

PinknerJs

JonesJm

WalkerJn

CleggS

2008 Utilization Of An Intracellular Bacterial Community Pathway In Klebsiella Pneumoniae Urinary Tract Infection And The Effects Of Fimk On Type 1 Pilus Expression. Infect Immun 76 3337 3345

30. SchillingJd

MartinSm

HungCs

LorenzRg

HultgrenSj

2003 Toll-Like Receptor 4 On Stromal And Hematopoietic Cells Mediates Innate Resistance To Uropathogenic Escherichia Coli. Proc Natl Acad Sci U S A 100 4203 4208

31. SongJ

DuncanMj

LiG

ChanC

GradyR

2007 A Novel Tlr4-Mediated Signaling Pathway Leading To Il-6 Responses In Human Bladder Epithelial Cells. Plos Pathog 3 E60

32. Svanborg EdenC

BrilesD

HagbergL

McgheeJ

MichalecS

1984 Genetic Factors In Host Resistance To Urinary Tract Infection. Infection 12 118 123

33. IngersollMa

KlineKa

NielsenHv

HultgrenSj

2008 G-Csf Induction Early In Uropathogenic Escherichia Coli Infection Of The Urinary Tract Modulates Host Immunity. Cell Microbiol 10 2568 2578

34. SivickKe

SchallerMa

SmithSn

MobleyHl

2010 The Innate Immune Response To Uropathogenic Escherichia Coli Involves Il-17a In A Murine Model Of Urinary Tract Infection. J Immunol 184 2065 2075

35. SongJ

BishopBl

LiG

GradyR

StapletonA

2009 Tlr4-Mediated Expulsion Of Bacteria From Infected Bladder Epithelial Cells. Proc Natl Acad Sci U S A 106 14966 14971

36. HedgesS

AndersonP

Lidin-JansonG

De ManP

SvanborgC

1991 Interleukin-6 Response To Deliberate Colonization Of The Human Urinary Tract With Gram-Negative Bacteria. Infect Immun 59 421 427

37. KoYc

MukaidaN

IshiyamaS

TokueA

KawaiT

1993 Elevated Interleukin-8 Levels In The Urine Of Patients With Urinary Tract Infections. Infect Immun 61 1307 1314

38. SchillingJd

MulveyMa

VincentCd

LorenzRg

HultgrenSj

2001 Bacterial Invasion Augments Epithelial Cytokine Responses To Escherichia Coli Through A Lipopolysaccharide-Dependent Mechanism. J Immunol 166 1148 1155

39. LundstedtAc

LeijonhufvudI

RagnarsdottirB

KarpmanD

AnderssonB

2007 Inherited Susceptibility To Acute Pyelonephritis: A Family Study Of Urinary Tract Infection. J Infect Dis 195 1227 1234

40. RagnarsdottirB

SamuelssonM

GustafssonMc

LeijonhufvudI

KarpmanD

2007 Reduced Toll-Like Receptor 4 Expression In Children With Asymptomatic Bacteriuria. J Infect Dis 196 475 484

41. Jones-CarsonJ

BalishE

UehlingDt

1999 Susceptibility Of Immunodeficient Gene-Knockout Mice To Urinary Tract Infection. J Urol 161 338 341

42. MalaviyaR

IkedaT

AbrahamSn

MalaviyaR

2004 Contribution Of Mast Cells To Bacterial Clearance And Their Proliferation During Experimental Cystitis Induced By Type 1 Fimbriated E. Coli. Immunol Lett 91 103 111

43. HaraokaM

HangL

FrendeusB

GodalyG

BurdickM

1999 Neutrophil Recruitment And Resistance To Urinary Tract Infection. J Infect Dis 180 1220 1229

44. DaleyJm

ThomayAa

ConnollyMd

ReichnerJs

AlbinaJe

2008 Use Of Ly6g-Specific Monoclonal Antibody To Deplete Neutrophils In Mice. J Leukoc Biol 83 64 70

45. HopkinsWj

Gendron-FitzpatrickA

BalishE

UehlingDt

1998 Time Course And Host Responses To Escherichia Coli Urinary Tract Infection In Genetically Distinct Mouse Strains. Infect Immun 66 2798 2802

46. SchillingJd

LorenzRg

HultgrenSj

2002 Effect Of Trimethoprim-Sulfamethoxazole On Recurrent Bacteriuria And Bacterial Persistence In Mice Infected With Uropathogenic Escherichia Coli. Infect Immun 70 7042 7049

47. EtoDs

SundsbakJl

MulveyMa

2006 Actin-Gated Intracellular Growth And Resurgence Of Uropathogenic Escherichia Coli. Cell Microbiol 8 704 717

48. MulveyMa

SchillingJd

HultgrenSj

2001 Establishment Of A Persistent Escherichia Coli Reservoir During The Acute Phase Of A Bladder Infection. Infect Immun 69 4572 4579

49. MysorekarIu

HultgrenSj

2006 Mechanisms Of Uropathogenic Escherichia Coli Persistence And Eradication From The Urinary Tract. Proc Natl Acad Sci U S A 103 14170 14175

50. HopkinsW

Gendron-FitzpatrickA

MccarthyDo

HaineJe

UehlingDt

1996 Lipopolysaccharide-Responder And Nonresponder C3h Mouse Strains Are Equally Susceptible To An Induced Escherichia Coli Urinary Tract Infection. Infect Immun 64 1369 1372

51. FerrySa

HolmSe

StenlundH

LundholmR

MonsenTj

2004 The Natural Course Of Uncomplicated Lower Urinary Tract Infection In Women Illustrated By A Randomized Placebo Controlled Study. Scand J Infect Dis 36 296 301

52. MabeckCe

1972 Treatment Of Uncomplicated Urinary Tract Infection In Non-Pregnant Women. Postgrad Med J 48 69 75

53. WatsonJ

RibletR

1974 Genetic Control Of Responses To Bacterial Lipopolysaccharides In Mice. I. Evidence For A Single Gene That Influences Mitogenic And Immunogenic Respones To Lipopolysaccharides. J Exp Med 140 1147 1161

54. AlteriCj

SmithSn

MobleyHl

2009 Fitness Of Escherichia Coli During Urinary Tract Infection Requires Gluconeogenesis And The Tca Cycle. Plos Pathog 5 E1000448

55. ShahinRd

EngbergI

HagbergL

Svanborg EdenC

1987 Neutrophil Recruitment And Bacterial Clearance Correlated With Lps Responsiveness In Local Gram-Negative Infection. J Immunol 138 3475 3480

56. HanssonS

HansonE

HjalmasK

HultengrenM

JodalU

1990 Follicular Cystitis In Girls With Untreated Asymptomatic Or Covert Bacteriuria. Journal Of Urology 143 330 332

57. MarshFp

BanerjeeR

PanchamiaP

1974 The Relationship Between Urinary Infection, Cystoscopic Appearance, And Pathology Of The Bladder In Man. Journal Of Clinical Pathology 27 297 307

58. RhenT

CidlowskiJa

2005 Antiinflammatory Action Of Glucocorticoids–New Mechanisms For Old Drugs. N Engl J Med 353 1711 1723

59. KleinM

PfisterHw

LeibSl

KoedelU

2009 Therapy Of Community-Acquired Acute Bacterial Meningitis: The Clock Is Running. Expert Opin Pharmacother 10 2609 2623

60. MatsukawaM

KumamotoY

HiroseT

MatsuuraA

1994 [Tissue Gamma/Delta T Cells In Experimental Urinary Tract Infection Relationship Between Other Immuno-Competent Cells]. Kansenshogaku Zasshi 68 1498 1511

61. GodalyG

HangL

FrendeusB

SvanborgC

2000 Transepithelial Neutrophil Migration Is Cxcr1 Dependent In Vitro And Is Defective In Il-8 Receptor Knockout Mice. J Immunol 165 5287 5294

62. De ManP

Van KootenC

AardenL

EngbergI

LinderH

1989 Interleukin-6 Induced At Mucosal Surfaces By Gram-Negative Bacterial Infection. Infect Immun 57 3383 3388

63. MysorekarIu

MulveyMa

HultgrenSj

GordonJi

2002 Molecular Regulation Of Urothelial Renewal And Host Defenses During Infection With Uropathogenic Escherichia Coli. J Biol Chem 277 7412 7419

64. WengnerAm

PitchfordSc

FurzeRc

RankinSm

2008 The Coordinated Action Of G-Csf And Elr+Cxc Chemokines In Neutrophil Mobilization During Acute Inflammation. Blood 111 42 49

65. HeldTk

MielkeMe

ChedidM

UngerM

TrautmannM

1998 Granulocyte Colony-Stimulating Factor Worsens The Outcome Of Experimental Klebsiella Pneumoniae Pneumonia Through Direct Interaction With The Bacteria. Blood 91 2525 2535

66. HedgesSr

BjarnadottirM

AgaceW

HangL

SvanborgC

1996 Immunoregulatory Cytokines Modify Escherichia Coli Induced Uroepithelial Cell Il-6 And Il-8 Responses. Cytokine 8 686 697

67. TakatsuK

NakajimaH

2008 Il-5 And Eosinophilia. Curr Opin Immunol 20 288 294

68. CarboneM

HastyDl

YiKc

RueJ

FeraMt

2002 Cytokine Induction In Murine Bladder Tissue By Type 1 Fimbriated Escherichia Coli. Ann N Y Acad Sci 963 332 335

69. RyanPj

WillsonT

AlexanderWs

Di RagoL

MifsudS

2001 The Multi-Organ Origin Of Interleukin-5 In The Mouse. Leukemia 15 1248 1255

70. TotemeyerS

FosterN

KaiserP

MaskellDj

BryantCe

2003 Toll-Like Receptor Expression In C3h/Hen And C3h/Hej Mice During Salmonella Enterica Serovar Typhimurium Infection. Infect Immun 71 6653 6657

71. Bernstein-HanleyI

BalsaraZr

UlmerW

CoersJ

StarnbachMn

2006 Genetic Analysis Of Susceptibility To Chlamydia Trachomatis In Mouse. Genes Immun 7 122 129

72. ChackerianAa

AltJm

PereraTv

DascherCc

BeharSm

2002 Dissemination Of Mycobacterium Tuberculosis Is Influenced By Host Factors And Precedes The Initiation Of T-Cell Immunity. Infect Immun 70 4501 4509

73. CartnerSc

SimeckaJw

LindseyJr

CassellGh

DavisJk

1995 Chronic Respiratory Mycoplasmosis In C3h/Hen And C57bl/6n Mice: Lesion Severity And Antibody Response. Infect Immun 63 4138 4142

74. HopkinsWj

ElkahwajiJ

KendziorskiC

MoserAr

BriggsPm

2009 Quantitative Trait Loci Associated With Susceptibility To Bladder And Kidney Infections Induced By Escherichia Coli In Female C3h/Hej Mice. J Infect Dis 199 355 361

75. HawnTr

ScholesD

LiSs

WangH

YangY

2009 Toll-Like Receptor Polymorphisms And Susceptibility To Urinary Tract Infections In Adult Women. Plos One 4 E5990

76. FerrieresL

HancockV

KlemmP

2007 Biofilm Exclusion Of Uropathogenic Bacteria By Selected Asymptomatic Bacteriuria Escherichia Coli Strains. Microbiology 153 1711 1719

77. SvanborgC

BergstenG

FischerH

GodalyG

GustafssonM

2006 Uropathogenic Escherichia Coli As A Model Of Host-Parasite Interaction. Curr Opin Microbiol 9 33 39

78. WrightKj

SeedPc

HultgrenSj

2005 Uropathogenic Escherichia Coli Flagella Aid In Efficient Urinary Tract Colonization. Infection And Immunity 73 7657 7668

79. HullRa

GillRe

HsuP

MinshewBh

FalkowS

1981 Construction And Expression Of Recombinant Plasmids Encoding Type 1 Or D-Mannose-Resistant Pili From A Urinary Tract Infection Escherichia Coli Isolate. Infect Immun 33 933 938

80. BrewerJa

KhorB

VogtSk

MugliaLm

FujiwaraH

2003 T-Cell Glucocorticoid Receptor Is Required To Suppress Cox-2-Mediated Lethal Immune Activation. Nat Med 9 1318 1322

81. SchrammR

SchaeferT

MengerMd

ThorlaciusH

2002 Acute Mast Cell-Dependent Neutrophil Recruitment In The Skin Is Mediated By Kc And Lfa-1: Inhibitory Mechanisms Of Dexamethasone. J Leukoc Biol 72 1122 1132