1887

Abstract

Most uropathogenic (UPEC) express type-1 fimbriae (T1F), a key virulence factor for urinary tract infection (UTI) in mice. Evidence that conclusively associates this pilus with uropathogenesis in humans has, however, been difficult to obtain. We used an experimental porcine model of cystitis to assess the role of T1F in larger mammals more closely related to humans. Thirty-one pigs were infected with UPEC strain UTI89 or its T1F deficient mutant, UTI89Δ, at inoculum titres of 10 to 10 colony forming units per millilitre. Urine and blood samples were collected and analysed 7 and 14 days post-inoculation, and whole bladders were removed at day 14 and analysed for uroepithelium-associated UPEC. All animals were consistently infected and reached high urine titres independent of inoculum titre. UTI89Δ successfully colonized the bladders of 1/6 pigs compared to 6/6 for the wild-type strain. Intracellular UPEC were detectable in low numbers in whole bladder explants. In conclusion, low doses of UPEC are able to establish robust infections in pigs, similar to what is presumed in humans. T1F are critical for UPEC to surpass initial bottlenecks during infection but may be dispensable once infection is established. While supporting the conclusions from mice studies regarding a general importance of T1F in successfully infecting the host, the porcine UTI models’ natural high, more human-like, susceptibility to infection, allowed us to demonstrate a pivotal role of T1F in initial establishment of infection upon a realistic low-inoculum introduction of UPEC in the bladder.

Funding
This study was supported by the:
  • Coloplast
    • Principle Award Recipient: ThomasEmil Andersen
  • Beckett-Fonden
    • Principle Award Recipient: ThomasKastberg Nielsen
  • Region of Southern Denmark (Award 17/33837)
    • Principle Award Recipient: ThomasEmil Andersen
  • Region of Southern Denmark (Award E-Fond: 150)
    • Principle Award Recipient: KristianStærk
  • This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License.
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2021-10-08
2021-10-25
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References

  1. Kornfält Isberg H. Increased adherence to treatment guidelines in patients with urinary tract infection in primary care: A retrospective study. PLoS One 2019; 14: [View Article] [PubMed]
    [Google Scholar]
  2. Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 2014; 28:1–13 [View Article] [PubMed]
    [Google Scholar]
  3. Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Dis Mon 2003; 49:71–82 [View Article] [PubMed]
    [Google Scholar]
  4. Stærk K. Uropathogenic Escherichia coli express type 1 fimbriae only in surface adherent populations under physiological growth conditions. J Infect Dis 2016; 213:386–394 [View Article] [PubMed]
    [Google Scholar]
  5. Greene SE, Hibbing ME, Janetka J, Chen SL, Hultgren SJ. Human urine decreases function and expression of type 1 pili in uropathogenic Escherichia coli. mBio 2015; 6: [View Article] [PubMed]
    [Google Scholar]
  6. Martinez JJ, Mulvey MA, Schilling JD, Pinkner JS, Hultgren SJ. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. Embo j 2000; 19:2803–2812 [View Article] [PubMed]
    [Google Scholar]
  7. Connell I, Agace W, Klemm P, Schembri M, Mărild S et al. Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract. Proc Natl Acad Sci U S A 1996; 93:9827–9832 [View Article] [PubMed]
    [Google Scholar]
  8. Hojati Z, Zamanzad B, Hashemzadeh M, Molaie R, Gholipour A. The FIMH gene in uropathogenic Escherichia coli strains isolated from patients with urinary tract infection. Jundishapur J Microbiol 2015; 8: [View Article] [PubMed]
    [Google Scholar]
  9. Wu XR, Sun TT, Medina JJ. 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 1996; 93:9630–9635 [View Article] [PubMed]
    [Google Scholar]
  10. Bahrani-Mougeot FK. Type 1 fimbriae and extracellular polysaccharides are preeminent uropathogenic Escherichia coli virulence determinants in the murine urinary tract. Mol Microbiol 2002; 45:1079–1093 [View Article] [PubMed]
    [Google Scholar]
  11. Nielubowicz GR, Mobley HL. Host-pathogen interactions in urinary tract infection. Nat Rev Urol 2010; 7:430–441 [View Article] [PubMed]
    [Google Scholar]
  12. Wright KJ, Seed PC, Hultgren SJ. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell Microbiol 2007; 9:2230–2241 [View Article] [PubMed]
    [Google Scholar]
  13. Anderson GG. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 2003; 301:105–107 [View Article] [PubMed]
    [Google Scholar]
  14. Justice SS. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc Natl Acad Sci U S A 2004; 101:1333–1338 [View Article] [PubMed]
    [Google Scholar]
  15. Hagan EC, Lloyd AL, Rasko DA, Faerber GJ, Mobley HLT. Escherichia coli global gene expression in urine from women with urinary tract infection. PLoS Pathog 2010; 6: [View Article] [PubMed]
    [Google Scholar]
  16. Meurens F. The pig: a model for human infectious diseases. Trends Microbiol 2012; 20:50–57 [View Article] [PubMed]
    [Google Scholar]
  17. Barber AE. Strengths and limitations of model systems for the study of urinary tract infections and related pathologies. Microbiol Mol Biol Rev 2016; 80:351–367 [View Article] [PubMed]
    [Google Scholar]
  18. Dawson HD. An in-depth comparison of the porcine, murine and human inflammasomes; lessons from the porcine genome and transcriptome. Vet Microbiol 2017; 202:2–15 [View Article] [PubMed]
    [Google Scholar]
  19. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 2013; 110:3507–3512 [View Article]
    [Google Scholar]
  20. Bélanger L. Escherichia coli from animal reservoirs as a potential source of human extraintestinal pathogenic E. coli. FEMS Immunol Med Microbiol 2011; 62:1–10 [View Article] [PubMed]
    [Google Scholar]
  21. Hung CS, Dodson KW, Hultgren SJ. A murine model of urinary tract infection. Nat Protoc 2009; 4:1230–1243 [View Article] [PubMed]
    [Google Scholar]
  22. Carey AJ. Urinary tract infection of mice to model human disease: Practicalities, implications and limitations. Crit Rev Microbiol 2016; 42:780–799 [View Article] [PubMed]
    [Google Scholar]
  23. Langermann S. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J Infect Dis 2000; 181:774–778 [View Article] [PubMed]
    [Google Scholar]
  24. Nielsen TK. A porcine model for urinary tract infection. Front Microbiol 2019; 10:2564 [View Article] [PubMed]
    [Google Scholar]
  25. Andersen TE. Escherichia coli uropathogenesis in vitro: invasion, cellular escape, and secondary infection analyzed in a human bladder cell infection model. Infect Immun 2012; 80:1858–1867 [View Article] [PubMed]
    [Google Scholar]
  26. Specific Pathogen Free system SPF SUS. https://spfsus.dk/en
  27. Khandige S, Asferg CA, Rasmussen KJ, Larsen MJ, Overgaard M et al. DamX controls reversible cell morphology switching in uropathogenic Escherichia coli. mBio 2016; 7: [View Article] [PubMed]
    [Google Scholar]
  28. Korhonen TK. Yeast cell agglutination by purified enterobacterial pili. FEMS Microbiol Lett 1979; 6:421–425 [View Article]
    [Google Scholar]
  29. Blango MG, Mulvey MA. Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Antimicrob Agents Chemother 2010; 54:1855–1863 [View Article] [PubMed]
    [Google Scholar]
  30. Berry RE, Klumpp DJ, Schaeffer AJ. Urothelial cultures support intracellular bacterial community formation by uropathogenic Escherichia coli. Infect Immun 2009; 77:2762–2772 [View Article] [PubMed]
    [Google Scholar]
  31. Söderhäll M. Induction of protective immunity after Escherichia coli bladder infection in primates. Dependence of the globoside-specific P-fimbrial tip adhesin and its cognate receptor. J Clin Invest 1997; 100:364–372 [View Article] [PubMed]
    [Google Scholar]
  32. Klemm P. Molecular characterization of the Escherichia coli asymptomatic bacteriuria strain 83972: the taming of a pathogen. Infect Immun 2006; 74:781–785 [View Article] [PubMed]
    [Google Scholar]
  33. Bergsten G. Do type 1 fimbriae promote inflammation in the human urinary tract. Cell Microbiol 2007; 9:1766–1781 [View Article] [PubMed]
    [Google Scholar]
  34. Parfentjev IA, Perlzweig WA. The composition of the urine of white mice. Journal of Biological Chemistry 1933; 100:551–555 [View Article]
    [Google Scholar]
  35. Perrier ET. Criterion values for urine-specific gravity and urine color representing adequate water intake in healthy adults. Eur J Clin Nutr 2017; 71:561–563 [View Article] [PubMed]
    [Google Scholar]
  36. Klein K. Antibacterial Effects of Drug Loaded Silicone Based Interpenetrating Networks, in Research Unit of Clinical Microbiology, Department of Clinical Research University of Southern Denmark; Denmark: 2019 p 111
    [Google Scholar]
  37. Klein K, Palarasah Y, Kolmos HJ, Møller-Jensen J, Andersen TE. Quantification of filamentation by uropathogenic Escherichia coli during experimental bladder cell infection by using semi-automated image analysis. J Microbiol Methods 2015; 109:110–116 [View Article] [PubMed]
    [Google Scholar]
  38. Berry MR, Mathews RJ, Ferdinand JR, Jing C, Loudon KW et al. Renal sodium gradient orchestrates a dynamic antibacterial defense zone. Cell 2017; 170:860–874 [View Article] [PubMed]
    [Google Scholar]
  39. Kaye D, Sobel JD. Persistence of intracellular bacteria in the urinary bladder. Clin Infect Dis 2014; 58:444 [View Article] [PubMed]
    [Google Scholar]
  40. Köves B, Wullt B. The roles of the host and the pathogens in urinary tract infections. European Urology Supplements 2016; 15:88–94 [View Article]
    [Google Scholar]
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