Uropathogenic Superinfection Enhances the Severity of Mouse Bladder Infection

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Urinary tract infections (UTIs) affect millions of women each year resulting in substantial morbidity and lost wages. Approximately 1.5 million women are referred to urology clinics suffering from chronic recurrent UTI on a yearly basis necessitating the use of prophylactic antibiotics. Frequent and recent sexual intercourse correlates with the development of UTI, a phenomenon referred to clinically as “honeymoon cystitis.” Here, using superinfection mouse models, we identified bacterial and host factors that influence the likelihood of developing chronic UTI. We discovered that superinfection leads to a higher rate of chronic UTI, which depended on bacterial replication within bladder cells combined with an immune response including inflammasome activation and cytokine release. These data suggest that bacterial inoculation into an acutely inflamed urinary tract is more likely to lead to severe UTI than bacterial presence in the absence of inflammation. Modification of these risk factors could lead to new therapeutics that prevent the development of recurrent UTI.

Vyšlo v časopise: Uropathogenic Superinfection Enhances the Severity of Mouse Bladder Infection. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004599
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004599

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1. FoxmanB (2003) Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Dis Mon 49: 53–70.

2. RosenbergM (1999) Pharmacoeconomics of treating uncomplicated urinary tract infections. Int J Antimicrob Agents 11: 247–251 discussion 261–244.

3. FoxmanB, BarlowR, D'ArcyH, GillespieB, SobelJD (2000) Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 10: 509–515.

4. FoxmanB, GillespieB, KoopmanJ, ZhangL, PalinK, et al. (2000) Risk factors for second urinary tract infection among college women. American journal of epidemiology 151: 1194–1205.

5. CzajaCA, StammWE, StapletonAE, RobertsPL, HawnTR, et al. (2009) Prospective cohort study of microbial and inflammatory events immediately preceding Escherichia coli recurrent urinary tract infection in women. The Journal of infectious diseases 200: 528–536.

6. StammWE, McKevittM, RobertsPL, WhiteNJ (1991) Natural history of recurrent urinary tract infections in women. Rev Infect Dis 13: 77–84.

7. StammWE (2002) Scientific and clinical challenges in the management of urinary tract infections. Am J Med 113 Suppl 1A: 1S–4S.

8. LauplandKB, RossT, PitoutJD, ChurchDL, GregsonDB (2007) Community-onset urinary tract infections: a population-based assessment. Infection 35: 150–153.

9. FerryS, HolmS, StenlundH, LundholmR, MonsenT (2004) The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scandinavian Journal of Infectious Diseases 36: 296–301.

10. MabeckCE (1972) Treatment of uncomplicated urinary tract infection in non-pregnant women. Postgraduate medical journal 48: 69–75.

11. EjrnaesK, SandvangD, LundgrenB, FerryS, HolmS, et al. (2006) Pulsed-Field Gel Electrophoresis Typing of Escherichia coli Strains from Samples Collected before and after Pivmecillinam or Placebo Treatment of Uncomplicated Community-Acquired Urinary Tract Infection in Women. Journal of Clinical Microbiology 44: 1776–1781.

12. FalagasME, KotsantisIK, VouloumanouEK, RafailidisPI (2009) Antibiotics versus placebo in the treatment of women with uncomplicated cystitis: A meta-analysis of randomized controlled trials. Journal of Infection 58: 91–102.

13. MarschallJ, ZhangL, FoxmanB, WarrenDK, HendersonJP, et al. (2012) Both host and pathogen factors predispose to Escherichia coli urinary-source bacteremia in hospitalized patients. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 54: 1692–1698.

14. GuptaK, HootonTM, StammWE (2005) Isolation of fluoroquinolone-resistant rectal Escherichia coli after treatment of acute uncomplicated cystitis. The Journal of antimicrobial chemotherapy 56: 243–246.

15. GuptaK, SahmDF, MayfieldD, StammWE (2001) Antimicrobial resistance among uropathogens that cause community-acquired urinary tract infections in women: a nationwide analysis. Clin Infect Dis 33: 89–94.

16. BouchillonS, HobanDJ, BadalR, HawserS (2012) Fluoroquinolone resistance among gram-negative urinary tract pathogens: global smart program results, 2009–2010. The open microbiology journal 6: 74–78.

17. ChenYH, KoWC, HsuehPR (2012) The role of fluoroquinolones in the management of urinary tract infections in areas with high rates of fluoroquinolone-resistant uropathogens. European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology 31: 1699–1704.

18. BuckleyRMJr, McGuckinM, MacGregorRR (1978) Urine bacterial counts after sexual intercourse. N Engl J Med 298: 321–324.

19. NicolleLE, HardingGK, PreiksaitisJ, RonaldAR (1982) The association of urinary tract infection with sexual intercourse. The Journal of infectious diseases 146: 579–583.

20. HootonTM, ScholesD, HughesJP, WinterC, RobertsPL, et al. (1996) A prospective study of risk factors for symptomatic urinary tract infection in young women. The New England journal of medicine 335: 468–474.

21. RosenDA, HootonTM, StammWE, HumphreyPA, HultgrenSJ (2007) Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med 4: e329.

22. ScholesD, HootonTM, RobertsPL, StapletonAE, GuptaK, et al. (2000) Risk factors for recurrent urinary tract infection in young women. The Journal of infectious diseases 182: 1177–1182.

23. FoxmanB, GeigerAM, PalinK, GillespieB, KoopmanJS (1995) First-time urinary tract infection and sexual behavior. Epidemiology 6: 162–168.

24. SchwartzDJ, ChenSL, HultgrenSJ, SeedPC (2011) Population Dynamics and Niche Distribution of Uropathogenic Escherichia coli during Acute and Chronic Urinary Tract Infection. Infect Immun 79: 4250–4259.

25. WaltersMS, LaneMC, VigilPD, SmithSN, WalkST, et al. (2011) Kinetics of Uropathogenic Escherichia coli Metapopulation Movement during Urinary Tract Infection. mBio 3: e00303–00311.

26. HannanTJ, TotsikaM, MansfieldKJ, MooreKH, SchembriMA, et al. (2012) Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev 36: 616–648.

27. Schwartz DJ, Hultgren SJ (2012) Uropathogenic Escherichia coli Virulence and Gene Regulation. In: Vasil ML, Darwin AJ, editors. Regulation of Bacterial Virulence. Washington, D.C.: ASM Press. pp. 135–155.

28. WuXR, SunTT, MedinaJJ (1996) In vitro binding of type 1-fimbriated Escherichia coli to uroplakins Ia and Ib: relation to urinary tract infections. Proc Natl Acad Sci U S A 93: 9630–9635.

29. MulveyMA, Lopez-BoadoYS, WilsonCL, RothR, ParksWC, et al. (1998) Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282: 1494–1497.

30. EtoDS, JonesTA, SundsbakJL, MulveyMA (2007) Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli. PLoS Pathog 3: e100.

31. SongJ, BishopBL, LiG, GradyR, StapletonA, et al. (2009) TLR4-mediated expulsion of bacteria from infected bladder epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 106: 14966–14971.

32. AndersonGG, PalermoJJ, SchillingJD, RothR, HeuserJ, et al. (2003) Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301: 105–107.

33. JusticeSS, HungC, TheriotJA, FletcherDA, AndersonGG, et al. (2004) Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc Natl Acad Sci USA 101: 1333–1338.

34. JusticeSS, HunstadDA, SeedPC, HultgrenSJ (2006) Filamentation by Escherichia coli subverts innate defenses during urinary tract infection. Proc Natl Acad Sci USA 103: 19884–19889.

35. RobinoL, ScavoneP, AraujoL, AlgortaG, ZuninoP, et al. (2013) Detection of intracellular bacterial communities in a child with Escherichia coli recurrent urinary tract infections. Pathogens and Disease 68: 78–81.

36. GarofaloCK, HootonTM, MartinSM, StammWE, PalermoJJ, et al. (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.

37. HannanTJ, MysorekarIU, HungCS, Isaacson-SchmidML, HultgrenSJ (2010) Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog 6.

38. HopkinsWJ, Gendron-FitzpatrickA, BalishE, UehlingDT (1998) Time course and host responses to Escherichia coli urinary tract infection in genetically distinct mouse strains. Infection and Immunity 66: 2798–2802.

39. KlineKA, SchwartzDJ, GilbertNM, HultgrenSJ, LewisAL (2012) Immune Modulation by Group B Streptococcus Influences Host Susceptibility to Urinary Tract Infection by Uropathogenic Escherichia coli. Infection and Immunity 80: 4186–4194.

40. MysorekarIU, HultgrenSJ (2006) Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proc Natl Acad Sci USA 103: 14170–14175.

41. SchillingJD, LorenzRG, HultgrenSJ (2002) Effect of trimethoprim-sulfamethoxazole on recurrent bacteriuria and bacterial persistence in mice infected with uropathogenic Escherichia coli. Infection and Immunity 70: 7042–7049.

42. SchlagerTA, LeGalloR, InnesD, HendleyJO, PetersCA (2011) B Cell Infiltration and Lymphonodular Hyperplasia in Bladder Submucosa of Patients With Persistent Bacteriuria and Recurrent Urinary Tract Infections. JURO 186: 2359–2364.

43. StemlerKM, CrockLW, LaiHH, MillsJC, GereauRWt, et al. (2013) Protamine sulfate induced bladder injury protects from distention induced bladder pain. J Urol 189: 343–351.

44. RudickCN, BillipsBK, PavlovVI, YaggieRE, SchaefferAJ, et al. (2010) Host-pathogen interactions mediating pain of urinary tract infection. The Journal of infectious diseases 201: 1240–1249.

45. HannanTJ, RobertsPL, RiehlTE, van der PostS, BinkleyJM, et al. (2014) Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis. EBIOM 1–12.

46. GuitonPS, HannanTJ, FordB, CaparonMG, HultgrenSJ (2013) Enterococcus faecalis overcomes foreign body-mediated inflammation to establish urinary tract infections. Infection and Immunity 81: 329–339.

47. ChenSL, HungCS, PinknerJS, WalkerJN, CusumanoCK, et al. (2009) Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding. Proceedings of the National Academy of Sciences of the United States of America 106: 22439–22444.

48. SchwartzDJ, KalasV, PinknerJS, ChenSL, SpauldingCN, et al. (2013) Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation. Proceedings of the National Academy of Sciences 110: 15530–15537.

49. PhanG, RemautH, WangT, AllenWJ, PirkerKF, et al. (2011) Crystal structure of the FimD usher bound to its cognate FimC-FimH substrate. Nature 474: 49–53.

50. Le TrongI, AprikianP, KiddBA, Forero-SheltonM, TchesnokovaV, et al. (2010) Structural basis for mechanical force regulation of the adhesin FimH via finger trap-like beta sheet twisting. Cell 141: 645–655.

51. NicholsonTF, WattsKM, HunstadDA (2009) OmpA of uropathogenic Escherichia coli promotes postinvasion pathogenesis of cystitis. Infection and Immunity 77: 5245–5251.

52. AndersonGG, GollerCC, JusticeS, HultgrenSJ, SeedPC (2010) Polysaccharide capsule and sialic acid-mediated regulation promote biofilm-like intracellular bacterial communities during cystitis. Infection and Immunity 78: 963–975.

53. DhakalBK, MulveyMA (2012) The UPEC Pore-Forming Toxin α-Hemolysin Triggers Proteolysis of Host Proteins to Disrupt Cell Adhesion, Inflammatory, and Survival Pathways. Cell Host and Microbe 11: 58–69.

54. GurC, Coppenhagen-GlazerS, RosenbergS, YaminR, EnkJ, et al. (2013) Natural Killer Cell-Mediated Host Defense against Uropathogenic E. coli Is Counteracted by Bacterial HemolysinA-Dependent Killing of NK Cells. Cell Host & Microbe 14: 664–674.

55. DhakalBK, MulveyMA (2012) The UPEC Pore-Forming Toxin α-Hemolysin Triggers Proteolysis of Host Proteins to Disrupt Cell Adhesion, Inflammatory, and Survival Pathways. Cell Host and Microbe 11: 58–69.

56. AhnH, KimJ, JeungE-B, LeeG-S (2014) Dimethyl sulfoxide inhibits NLRP3 inflammasome activation. Immunobiology 219: 315–322.

57. ParsonsCL, BoychukD, JonesS, HurstR, CallahanH (1990) Bladder surface glycosaminoglycans: an epithelial permeability barrier. J Urol 143: 139–142.

58. EtoDS, GordonHB, DhakalBK, JonesTA, MulveyMA (2008) Clathrin, AP-2, and the NPXY-binding subset of alternate endocytic adaptors facilitate FimH-mediated bacterial invasion of host cells. Cellular Microbiology 10: 2553–2567.

59. MossmanKL, MianMF, LauzonNM, GylesCL, LichtyB, et al. (2008) Cutting edge: FimH adhesin of type 1 fimbriae is a novel TLR4 ligand. J Immunol 181: 6702–6706.

60. EppigJT, BlakeJA, BultCJ, KadinJA, RichardsonJE (2012) The Mouse Genome Database (MGD): comprehensive resource for genetics and genomics of the laboratory mouse. Nucleic Acids Res 40: D881–886.

61. Huang daW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57.

62. Huang daW, ShermanBT, LempickiRA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37: 1–13.

63. ThumbikatP, WaltenbaughC, SchaefferAJ, KlumppDJ (2006) Antigen-specific responses accelerate bacterial clearance in the bladder. Journal of immunology (Baltimore, Md: 1950) 176: 3080–3086.

64. HootonTM (2001) Recurrent urinary tract infection in women. Int J Antimicrob Agents 17: 259–268.

65. ChenSL, WuM, HendersonJP, HootonTM, HibbingME, et al. (2013) Genomic Diversity and Fitness of E. coli Strains Recovered from the Intestinal and Urinary Tracts of Women with Recurrent Urinary Tract Infection. Science Translational Medicine 5: 184ra160.

66. MabbettAN, UlettGC, WattsRE, TreeJJ, TotsikaM, et al. (2009) Virulence properties of asymptomatic bacteriuria Escherichia coli. International journal of medical microbiology: IJMM 299: 53–63.

67. CusumanoCK, PinknerJS, HanZ, GreeneSE, FordBA, et al. (2011) Treatment and Prevention of Urinary Tract Infection with Orally Active FimH Inhibitors. Sci Transl Med 3: 109ra115.

68. SchwardtO, RabbaniS, HartmannM, AbgottsponD, WittwerM, et al. (2011) Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists. Bioorg Med Chem 19: 6454–6473.

69. KleinT, AbgottsponD, WittwerM, RabbaniS, HeroldJ, et al. (2010) FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation. Journal of medicinal chemistry 53: 8627–8641.

70. HanZ, PinknerJS, FordB, ObermannR, NolanW, et al. (2010) Structure-based drug design and optimization of mannoside bacterial FimH antagonists. J Med Chem 53: 4779–4792.

71. WrightKJ, SeedPC, HultgrenSJ (2005) Uropathogenic Escherichia coli flagella aid in efficient urinary tract colonization. Infection and Immunity 73: 7657–7668.

72. HungC-S, DodsonKW, HultgrenSJ (2009) A murine model of urinary tract infection. Nature protocols 4: 1230–1243.