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Bacteriophages of the lower urinary tract

Abstract

The discovery of bacteria in the female urinary bladder has fundamentally changed current dogma regarding the urinary tract and related urinary disorders. Previous research characterized many of the bacterial components of the female urinary tract, but the viral fraction of this community is largely unknown. Viruses within the human microbiota far outnumber bacterial cells, with the most abundant viruses being those that infect bacteria (bacteriophages). Similar to observations within the microbiota of the gut and oral cavity, preliminary surveys of the urinary tract and bladder microbiota indicate a rich diversity of uncharacterized bacteriophage (phage) species. Phages are vital members of the microbiota, having critical roles in shaping bacterial metabolism and community structure. Although phages have been discovered in the urinary tract, such as phages that infect Escherichia coli, sampling them is challenging owing to low biomass, possible contamination when using non-invasive methods and the invasiveness of methods that reduce the potential for contamination. Phages could influence bladder health, but an understanding of the association between phage communities, bacterial populations and bladder health is in its infancy. However, evidence suggests that phages can defend the host against pathogenic bacteria and, therefore, modulation of the microbiome using phages has therapeutic potential for lower urinary tract symptoms. Furthermore, as natural predators of bacteria, phages have garnered renewed interest for their use as antimicrobial agents, for instance, in the treatment of urinary tract infections.

Key points

  • Bacteriophages (phages) are abundant members of the microbiota of the lower urinary tract.

  • Active or lytic phages have been isolated from urine samples, but the majority of phages within the urinary microbiota persist through dormant infections, the lysogenic life cycle.

  • Evidence suggests that phages have a role in modulating the composition of the urinary microbiota, similar to that observed in microbiota of other organs of the human body.

  • Phage therapy, or the use of phages to treat pathogenic bacterial infections, is an active area of research within urology given their potential use to treat urinary tract infections.

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Fig. 1: Lytic and lysogenic cycles of phages and their impact on microbiota.
Fig. 2: The process of transduction.
Fig. 3: Phage tail morphologies.
Fig. 4: Bacteriophage Greed, isolated from catheterized urine microbiome sample.

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References

  1. Chibani-Chennoufi, S., Bruttin, A., Dillmann, M.-L. & Brussow, H. Phage-host interaction: an ecological perspective. J. Bacteriol. 186, 3677–3686 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Breitbart, M., Bonnain, C., Malki, K. & Sawaya, N. A. Phage puppet masters of the marine microbial realm. Nat. Microbiol. 3, 754–766 (2018).

    CAS  PubMed  Google Scholar 

  3. Williamson, K. E., Radosevich, M. & Wommack, K. E. Abundance and diversity of viruses in six Delaware soils. Appl. Environ. Microbiol. 71, 3119–3125 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Williamson, K. E., Fuhrmann, J. J., Wommack, K. E. & Radosevich, M. Viruses in soil ecosystems: an unknown quantity within an unexplored territory. Annu. Rev. Virol. 4, 201–219 (2017).

    CAS  PubMed  Google Scholar 

  5. Bruder, K. et al. Freshwater metaviromics and bacteriophages: a current assessment of the state of the art in relation to bioinformatic challenges. Evol. Bioinform. Online 12, 25–33 (2016).

    PubMed  PubMed Central  Google Scholar 

  6. Prestel, E., Regeard, C., Salamitou, S., Neveu, J. & Dubow, M. S. The bacteria and bacteriophages from a Mesquite Flats site of the Death Valley desert. Antonie Van Leeuwenhoek 103, 1329–1341 (2013).

    PubMed  Google Scholar 

  7. Luhtanen, A.-M. et al. Isolation and characterization of phage–host systems from the Baltic Sea ice. Extremophiles 18, 121–130 (2014).

    CAS  PubMed  Google Scholar 

  8. Nigro, O. D. et al. Viruses in the oceanic basement. mBio 8, e02129–16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Koskella, B. & Parr, N. The evolution of bacterial resistance against bacteriophages in the horse chestnut phyllosphere is general across both space and time. Phil. Trans. R. Soc. B 370, 20140297 (2015).

    PubMed  Google Scholar 

  10. Pramono, A. K. et al. Discovery and complete genome sequence of a bacteriophage from an obligate intracellular symbiont of a cellulolytic protist in the termite gut. Microbes Environ. 32, 112–117 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Moreno, P. S. et al. Characterisation of the canine faecal virome in healthy dogs and dogs with acute diarrhoea using shotgun metagenomics. PLOS ONE 12, e0178433 (2017).

    PubMed  PubMed Central  Google Scholar 

  12. Barr, J. J. A bacteriophages journey through the human body. Immunol. Rev. 279, 106–122 (2017).

    CAS  PubMed  Google Scholar 

  13. Navarro, F. & Muniesa, M. Phages in the human body. Front. Microbiol. 8, 566 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. Nguyen, S. et al. Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers. mBio 8, e01874–17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Górski, A. et al. Bacteriophage translocation. FEMS Immunol. Med. Microbiol. 46, 313–319 (2006).

    PubMed  Google Scholar 

  16. Hayes, S., Mahony, J., Nauta, A. & van Sinderen, D. Metagenomic approaches to assess bacteriophages in various environmental niches. Viruses 9, 127 (2017).

    PubMed Central  Google Scholar 

  17. Kim, K.-H. & Bae, J.-W. Amplification methods bias metagenomic libraries of uncultured single-stranded and double-stranded DNA viruses. Appl. Environ. Microbiol. 77, 7663–7668 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Parras-Moltó, M., Rodríguez-Galet, A., Suárez-Rodríguez, P. & López-Bueno, A. Evaluation of bias induced by viral enrichment and random amplification protocols in metagenomic surveys of saliva DNA viruses. Microbiome 6, 119 (2018).

    PubMed  PubMed Central  Google Scholar 

  19. Yilmaz, S., Allgaier, M. & Hugenholtz, P. Multiple displacement amplification compromises quantitative analysis of metagenomes. Nat. Methods 7, 943–944 (2010).

    CAS  PubMed  Google Scholar 

  20. Kristensen, D. M. et al. Orthologous gene clusters and taxon signature genes for viruses of prokaryotes. J. Bacteriol. 195, 941–950 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Adriaenssens, E. M. & Cowan, D. A. Using signature genes as tools to assess environmental viral ecology and diversity. Appl. Environ. Microbiol. 80, 4470–4480 (2014).

    PubMed  PubMed Central  Google Scholar 

  22. Roux, S., Hallam, S. J., Woyke, T. & Sullivan, M. B. Viral dark matter and virus-host interactions resolved from publicly available microbial genomes. eLife 4, e08490 (2015).

    PubMed Central  Google Scholar 

  23. Paez-Espino, D. et al. IMG/VR: a database of cultured and uncultured DNA viruses and retroviruses. Nucleic Acids Res. 45, D457–D465 (2017).

    CAS  PubMed  Google Scholar 

  24. Paez-Espino, D. et al. Uncovering Earth’s virome. Nature 536, 425–430 (2016).

    CAS  PubMed  Google Scholar 

  25. Minot, S. et al. Rapid evolution of the human gut virome. Proc. Natl Acad. Sci. USA 110, 12450–12455 (2013).

    CAS  PubMed  Google Scholar 

  26. Minot, S. et al. The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lim, E. S. et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat. Med. 21, 1228–1234 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ogilvie, L. A. & Jones, B. V. The human gut virome: a multifaceted majority. Front. Microbiol. 6, 918 (2015).

    PubMed  PubMed Central  Google Scholar 

  30. Manrique, P. et al. Healthy human gut phageome. Proc. Natl Acad. Sci. USA 113, 10400–10405 (2016).

    CAS  PubMed  Google Scholar 

  31. Manrique, P., Dills, M. & Young, M. The human gut phage community and its implications for health and disease. Viruses 9, 141 (2017).

    PubMed Central  Google Scholar 

  32. Rani, A. et al. A diverse virome in kidney transplant patients contains multiple viral subtypes with distinct polymorphisms. Sci. Rep. 6, 33327 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Garretto, A., Thomas-White, K., Wolfe, A. J. & Putonti, C. Detecting viral genomes in the female urinary microbiome. J. Gen. Virol. 99, 1141–1146 (2018).

    CAS  PubMed  Google Scholar 

  34. Thannesberger, J. et al. Viruses comprise an extensive pool of mobile genetic elements in eukaryote cell cultures and human clinical samples. FASEB J. 31, 1987–2000 (2017).

    CAS  PubMed  Google Scholar 

  35. Santiago-Rodriguez, T. M., Ly, M., Bonilla, N. & Pride, D. T. The human urine virome in association with urinary tract infections. Front. Microbiol. 6, 14 (2015).

    PubMed  PubMed Central  Google Scholar 

  36. Moustafa, A. et al. Microbial metagenome of urinary tract infection. Sci. Rep. 8, 4333 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Huttenhower, C. et al. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

    CAS  Google Scholar 

  38. Aagaard, K. et al. The Human Microbiome Project strategy for comprehensive sampling of the human microbiome and why it matters. FASEB J. 27, 1012–1022 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Thomas-White, K., Brady, M., Wolfe, A. J. & Mueller, E. R. The bladder is not sterile: history and current discoveries on the urinary microbiome. Curr. Bladder Dysfunct. Rep. 11, 18–24 (2016).

    PubMed  PubMed Central  Google Scholar 

  40. Fouts, D. E. et al. Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. J. Transl Med. 10, 174 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wolfe, A. J. et al. Evidence of uncultivated bacteria in the adult female bladder. J. Clin. Microbiol. 50, 1376–1383 (2012).

    PubMed  PubMed Central  Google Scholar 

  42. Brubaker, L. et al. Urinary bacteria in adult women with urgency urinary incontinence. Int. Urogynecol. J. 25, 1179–1184 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. Hilt, E. E. et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J. Clin. Microbiol. 52, 871–876 (2014).

    PubMed  PubMed Central  Google Scholar 

  44. Pearce, M. M. et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio 5, e01283–14 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Pearce, M. M. et al. The female urinary microbiome in urgency urinary incontinence. Am. J. Obstet. Gynecol. 213, 347.e1–347.e11 (2015).

    Google Scholar 

  46. Thomas-White, K., Fok, C., Mueller, E. R., Wolfe, A. J. & Brubaker, L. Pre-operative urinary microbiome reveals post-operative urinary tract infection risk. Neurourol. Urodynam. 34, S21–S22 (2015).

    Google Scholar 

  47. Karstens, L. et al. Does the urinary microbiome play a role in urgency urinary incontinence and its severity? Front. Cell. Infect. Microbiol. 6, 78 (2016).

    PubMed  PubMed Central  Google Scholar 

  48. Ackerman, A. L. & Underhill, D. M. The mycobiome of the human urinary tract: potential roles for fungi in urology. Ann. Transl Med. 5, 31–31 (2017).

    PubMed  PubMed Central  Google Scholar 

  49. Whiteside, S. A., Razvi, H., Dave, S., Reid, G. & Burton, J. P. The microbiome of the urinary tract — a role beyond infection. Nat. Rev. Urol. 12, 81–90 (2015).

    PubMed  Google Scholar 

  50. Fok, C. S. et al. Day of surgery urine cultures identify urogynecologic patients at increased risk for postoperative urinary tract infection. J. Urol. 189, 1721–1724 (2013).

    PubMed  Google Scholar 

  51. Nienhouse, V. et al. Interplay between bladder microbiota and urinary antimicrobial peptides: mechanisms for human urinary tract infection risk and symptom severity. PLOS ONE 9, e114185 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. Thomas-White, K. J. et al. Incontinence medication response relates to the female urinary microbiota. Int. Urogynecol. J. 27, 723–733 (2016).

    PubMed  Google Scholar 

  53. Fok, C. S. et al. Urinary symptoms are associated with certain urinary microbes in urogynecologic surgical patients. Int. Urogynecol. J. 29, 1765–1771 (2018).

    PubMed  Google Scholar 

  54. Thomas-White, K. J. et al. Urinary microbes and postoperative urinary tract infection risk in urogynecologic surgical patients. Int. Urogynecol. J. 29, 1797–1805 (2018).

    PubMed  Google Scholar 

  55. Brubaker, L. & Wolfe, A. J. Microbiota in 2016: associating infection and incontinence with the female urinary microbiota. Nat. Rev. Urol. 14, 72–74 (2017).

    PubMed  PubMed Central  Google Scholar 

  56. Mueller, E. R., Wolfe, A. J. & Brubaker, L. Female urinary microbiota. Curr. Opin. Urol. 27, 282–286 (2017).

    PubMed  PubMed Central  Google Scholar 

  57. Thomas-White, K. Culturing of female bladder bacteria reveals an interconnected urogenital microbiome. Nat. Commun. 9, 8350 (2018).

    Google Scholar 

  58. Wylie, K. M. et al. Metagenomic analysis of double-stranded DNA viruses in healthy adults. BMC Biol. 12, 71 (2014).

    PubMed  PubMed Central  Google Scholar 

  59. Lloyd-Price, J., Abu-Ali, G. & Huttenhower, C. The healthy human microbiome. Genome Med. 8, 51 (2016).

    PubMed  PubMed Central  Google Scholar 

  60. Wagner, J. et al. Bacteriophages in gut samples from pediatric Crohn’s disease patients: metagenomic analysis using 454 Pyrosequencing. Inflamm. Bowel Dis. 19, 1598–1608 (2013).

    PubMed  Google Scholar 

  61. Zuo, T. et al. Gut mucosal virome alterations in ulcerative colitis. Gut https://doi.org/10.1136/gutjnl-2018-318131 (2019).

    Article  PubMed  Google Scholar 

  62. Ma, Y., You, X., Mai, G., Tokuyasu, T. & Liu, C. A human gut phage catalog correlates the gut phageome with type 2 diabetes. Microbiome 6, 24 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. Foulongne, V. et al. Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing. PLOS ONE 7, e38499 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Pride, D. T. et al. Evidence of a robust resident bacteriophage population revealed through analysis of the human salivary virome. ISME J. 6, 915–926 (2012).

    CAS  PubMed  Google Scholar 

  65. Ly, M. et al. Altered oral viral ecology in association with periodontal disease. mBio 5, e01133–14 (2014).

    PubMed  PubMed Central  Google Scholar 

  66. Hannigan, G. D. et al. The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome. mBio 6, e01578–15 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Hannigan, G. D. et al. Evolutionary and functional implications of hypervariable loci within the skin virome. PeerJ 5, e2959 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Pérez-Brocal, V. & Moya, A. The analysis of the oral DNA virome reveals which viruses are widespread and rare among healthy young adults in Valencia (Spain). PLOS ONE 13, e0191867 (2018).

    PubMed  PubMed Central  Google Scholar 

  69. Thomas-White, K. J. et al. Evaluation of the urinary microbiota of women with uncomplicated stress urinary incontinence. Am J. Obstet. Gynecol. 216, 55.e1–55.e16 (2017).

    Google Scholar 

  70. Bajic, P. et al. Male bladder microbiome relates to lower urinary tract symptoms. Eur. Urol. Focus https://doi.org/10.1016/j.euf.2018.08.001 (2018).

    Article  PubMed  Google Scholar 

  71. Kramer, H. et al. Diversity of the midstream urine microbiome in adults with chronic kidney disease. Int. Urol. Nephrol. 50, 1123–1130 (2018).

    PubMed  PubMed Central  Google Scholar 

  72. Hobbs, Z. & Abedon, S. T. Diversity of phage infection types and associated terminology: the problem with ‘Lytic or lysogenic’. FEMS Microbiol. Lett. 363, fnw047 (2016).

    PubMed  Google Scholar 

  73. Koskella, B. & Meaden, S. Understanding bacteriophage specificity in natural microbial communities. Viruses 5, 806–823 (2013).

    PubMed  PubMed Central  Google Scholar 

  74. Young, R. Phage lysis: Three steps, three choices, one outcome. J. Microbiol. 52, 243–258 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Little, J. in Phages Their Role in Bacterial Pathogenesis and Biotechnology (eds Waldor, M., Friedman, D. & Adhya, S.) 37–54 (ASM Press, 2005).

  76. Abedon, S. T. Bacteriophage Ecology: Population Growth, Evolution, and Impact of Bacterial Viruses (Cambridge Univ. Press, 2008).

  77. Erez, Z. et al. Communication between viruses guides lysis-lysogeny decisions. Nature 541, 488–493 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Calendar, R. The Bacteriophages (Oxford Univ. Press, 2006).

  79. Fuhrman, J. A. Marine viruses and their biogeochemical and ecological effects. Nature 399, 541–548 (1999).

    CAS  PubMed  Google Scholar 

  80. Suttle, C. A. Viruses in the sea. Nature 437, 356–361 (2005).

    CAS  PubMed  Google Scholar 

  81. Clokie, M. R. J., Millard, A. D., Letarov, A. V. & Heaphy, S. Phages in nature. Bacteriophage 1, 31–45 (2011).

    PubMed  PubMed Central  Google Scholar 

  82. Buckling, A. & Rainey, P. B. Antagonistic coevolution between a bacterium and a bacteriophage. Proc. Biol. Sci. 269, 931–936 (2002).

    PubMed  PubMed Central  Google Scholar 

  83. Rodriguez-Valera, F. et al. Explaining microbial population genomics through phage predation. Nat. Rev. Microbiol. 7, 828–836 (2009).

    CAS  PubMed  Google Scholar 

  84. Koskella, B. & Brockhurst, M. A. Bacteria-phage coevolution as a driver of ecological and evolutionary processes in microbial communities. FEMS Microbiol. Rev. 38, 916–931 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Tellier, A., Moreno-Gámez, S. & Stephan, W. Speed of adaptation and genomic footprints of host-parasite coevolution under arms race and trench warfare dynamics. Evolution 68, 2211–2224 (2014).

    PubMed  Google Scholar 

  86. Braga, L. P. P., Soucy, S. M., Amgarten, D. E., da Silva, A. M. & Setubal, J. C. Bacterial diversification in the light of the interactions with phages: the genetic symbionts and their role in ecological speciation. Front. Ecol. Evol. 6, 6 (2018).

    Google Scholar 

  87. Scanlan, P. D. Bacteria–bacteriophage coevolution in the human gut: implications for microbial diversity and functionality. Trends Microbiol. 25, 614–623 (2017).

    CAS  PubMed  Google Scholar 

  88. Hosseinidoust, Z., van de Ven, T. G. M. & Tufenkji, N. Evolution of Pseudomonas aeruginosa virulence as a result of phage predation. Appl. Environ. Microbiol. 79, 6110–6116 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wendling, C. C. et al. Tripartite species interaction: eukaryotic hosts suffer more from phage susceptible than from phage resistant bacteria. BMC Evol. Biol. 17, 98 (2017).

    PubMed  PubMed Central  Google Scholar 

  90. Wagner, P. L. & Waldor, M. K. Bacteriophage control of bacterial virulence. Infect. Immun. 70, 3985–3993 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Casas, V. & Maloy, S. Role of bacteriophage-encoded exotoxins in the evolution of bacterial pathogens. Future Microbiol. 6, 1461–1473 (2011).

    CAS  PubMed  Google Scholar 

  92. Starr, M. et al. Hemolytic-uremic syndrome following urinary tract infection with enterohemorrhagic Escherichia coli: case report and review. Clin. Infect. Dis. 27, 310–315 (1998).

    CAS  PubMed  Google Scholar 

  93. Gadea, M. et al. Two cases of urinary tract infection caused by Shiga toxin-producing Escherichia coli O157:H7 strains. Rev. Argent. Microbiol. 44, 94–96 (2012).

    Google Scholar 

  94. Toval, F. et al. Characterization of urinary tract infection-associated shiga toxin-producing Escherichia coli. Infect. Immun. 82, 4631–4642 (2014).

    PubMed  PubMed Central  Google Scholar 

  95. Harrison, E. & Brockhurst, M. A. Ecological and evolutionary benefits of temperate phage: what does or doesn’t kill you makes you stronger. BioEssays 39, 1700112 (2017).

    Google Scholar 

  96. Touchon, M., Moura de Sousa, J. A. & Rocha, E. P. Embracing the enemy: the diversification of microbial gene repertoires by phage-mediated horizontal gene transfer. Curr. Opin. Microbiol. 38, 66–73 (2017).

    CAS  PubMed  Google Scholar 

  97. Drexler, H. Transduction by bacteriophage T1. Proc. Natl Acad. Sci. USA 66, 1083–1088 (1970).

    CAS  PubMed  Google Scholar 

  98. Modi, S. R., Lee, H. H., Spina, C. S. & Collins, J. J. Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499, 219–222 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Abeles, S. R., Ly, M., Santiago-Rodriguez, T. M. & Pride, D. T. Effects of long term antibiotic therapy on human oral and fecal viromes. PLOS ONE 10, e0134941 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. Enault, F. et al. Phages rarely encode antibiotic resistance genes: a cautionary tale for virome analyses. ISME J. 11, 237–247 (2017).

    CAS  PubMed  Google Scholar 

  101. Lood, R., Ertürk, G. & Mattiasson, B. Revisiting antibiotic resistance spreading in wastewater treatment plants — bacteriophages as a much neglected potential transmission vehicle. Front. Microbiol. 8, 2298 (2017).

    PubMed  PubMed Central  Google Scholar 

  102. Keen, E. C. et al. Novel “superspreader” bacteriophages promote horizontal gene transfer by transformation. mBio 8, e02115–16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Hatfull, G. F. Dark matter of the biosphere: the amazing world of bacteriophage diversity. J. Virol. 89, 8107–8110 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang, J., Gao, Y. & Zhao, F. Phage-bacteria interaction network in human oral microbiome: Human oral virome. Environ. Microbiol. 18, 2143–2158 (2016).

    CAS  PubMed  Google Scholar 

  105. Shapiro, J. W. & Putonti, C. Gene co-occurrence networks reflect bacteriophage ecology and evolution. mBio 9, e01870–17 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. Echavarria, M., Forman, M., Ticehurst, J., Dumler, J. S. & Charache, P. PCR method for detection of adenovirus in urine of healthy and human immunodeficiency virus-infected individuals. J. Clin. Microbiol. 36, 3323–3326 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lion, T. Adenovirus infections in immunocompetent and immunocompromised patients. Clin. Microbiol. Rev. 27, 441–462 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Tan, S. K., Relman, D. A. & Pinsky, B. A. The human virome: implications for clinical practice in transplantation medicine. J. Clin. Microbiol. 55, 2884–2893 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Chang, H. et al. High incidence of JC viruria in JC-seropositive older individuals. J. Neurovirol. 8, 447–451 (2002).

    CAS  PubMed  Google Scholar 

  110. Hirsch, H. H., Kardas, P., Kranz, D. & Leboeuf, C. The human JC polyomavirus (JCPyV): virological background and clinical implications. APMIS 121, 685–727 (2013).

    CAS  PubMed  Google Scholar 

  111. Rinaldo, C. H., Tylden, G. D. & Sharma, B. N. The human polyomavirus BK (BKPyV): virological background and clinical implications. APMIS 121, 728–745 (2013).

    CAS  PubMed  Google Scholar 

  112. Tshomo, U. et al. Evaluation of the performance of human papillomavirus testing in paired urine and clinician-collected cervical samples among women aged over 30 years in Bhutan. Virol. J. 14, 74 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. Iwasawa, A. et al. Presence of human papillomavirus 6/11 DNA in condyloma acuminatum of the urinary bladder. Urol. Int. 48, 235–238 (1992).

    CAS  PubMed  Google Scholar 

  114. Karim, R. Z., Rose, B. R., Brammah, S. & Scolyer, R. A. Condylomata acuminata of the urinary bladder with HPV 11. Pathology 37, 176–178 (2005).

    PubMed  Google Scholar 

  115. Chrisofos, M., Skolarikos, A., Lazaris, A., Bogris, S. & Deliveliotis, C. HPV 16/18-associated condyloma acuminatum of the urinary bladder: first international report and review of literature. Int. J. STD AIDS 15, 836–838 (2004).

    CAS  PubMed  Google Scholar 

  116. Murray, A. J., Bivalacqua, T. J. & Sopko, N. A. Innumerable Condyloma Acuminatum tumors of the bladder. Urol. Case Rep. 12, 76–77 (2017).

    PubMed  PubMed Central  Google Scholar 

  117. Ma, Y. et al. Human papillomavirus community in healthy persons, defined by metagenomics analysis of Human Microbiome Project shotgun sequencing data sets. J. Virol. 88, 4786–4797 (2014).

    PubMed  PubMed Central  Google Scholar 

  118. d’Herelle, F. Sur un microbe invisible antagoniste des bacilles dysenteriques [French]. C. R. Acad. Sci. 165, 373 (1917).

    Google Scholar 

  119. Brown-Jaque, M., Muniesa, M. & Navarro, F. Bacteriophages in clinical samples can interfere with microbiological diagnostic tools. Sci. Rep. 6, 33000 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Jalil, M. B., Al-Hmudi, H. A., Al-Alsaad, L. A. & Abdul-Hussein, Z. R. Isolation and characterization of bacteriophages against multiple drug resistant Pseudomonas aeruginosa with using the bacteriophage as a therpy in the mice model. Int. J. Dev. Res. 7, 11519 (2017).

    Google Scholar 

  121. Dallas, S. D. & Kingsbery, L. Bacteriophage plaques on primary isolation media of a urine culture growing Escherichia coli. Clin. Microbiol. Newsl. 19, 53–56 (1997).

    Google Scholar 

  122. Malki, K. et al. Seven bacteriophages isolated from the female urinary microbiota. Genome Announc. 4, e01003–16 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. Smith, R., O’Hara, M., Hobman, J. L. & Millard, A. D. Draft genome sequences of 14 Escherichia coli phages isolated from cattle slurry. Genome Announc. 3, e01364–15 (2015).

    PubMed  PubMed Central  Google Scholar 

  124. Putonti, C., Garretto, A., Shapiro, J. W. & Wolfe, A. J. The role of bacterial viruses in the female urinary microbiome. Female Pelv. Med. Reconstr. Surg. 23, S39–S40 (2017).

    Google Scholar 

  125. Edlund, A., Santiago-Rodriguez, T. M., Boehm, T. K. & Pride, D. T. Bacteriophage and their potential roles in the human oral cavity. J. Oral Microbiol. 7, 27423 (2015).

    PubMed  Google Scholar 

  126. Kim, M.-S. & Bae, J.-W. Lysogeny is prevalent and widely distributed in the murine gut microbiota. ISME J. 12, 1127–1141 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Price, T. K. et al. Genome sequences and annotation of two urinary isolates of E. coli. Stand. Genomic Sci. 11, 79 (2016).

    PubMed  PubMed Central  Google Scholar 

  128. Malki, K. et al. Genomes of Gardnerella strains reveal an abundance of prophages within the bladder microbiome. PLOS ONE 11, e0166757 (2016).

    PubMed  PubMed Central  Google Scholar 

  129. Miller-Ensminger, T. et al. Bacteriophages of the urinary microbiome. J. Bacteriol. 200, e00738–17 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Lewis, D. A. et al. The human urinary microbiome; bacterial DNA in voided urine of asymptomatic adults. Front. Cell. Infect. Microbiol. 3, 41 (2013).

    PubMed  PubMed Central  Google Scholar 

  131. Gottschick, C. et al. The urinary microbiota of men and women and its changes in women during bacterial vaginosis and antibiotic treatment. Microbiome 5, 99 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. Perkins, D., Metwally, A. & Finn, P. Microbes everywhere. Presented at the 2017 Great Lakes Bioinformatics Conference 2017 at the University of Illinois, Chicago, IL, USA (2017).

  133. Khasriya, R. et al. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J. Clinl Microbiol. 51, 2054–2062 (2013).

    Google Scholar 

  134. Price, T. K. et al. The clinical urine culture: enhanced techniques improve detection of clinically relevant microorganisms. J. Clin. Microbiol. 54, 1216–1222 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Bao, Y. et al. Questions and challenges associated with studying the microbiome of the urinary tract. Ann. Transl Med. 5, 33–33 (2017).

    PubMed  PubMed Central  Google Scholar 

  136. Gangping, L. et al. Diversity of duodenal and rectal microbiota in biopsy tissues and luminal contents in healthy volunteers. J. Microbiol. Biotechnol. 25, 1136–1145 (2015).

    Google Scholar 

  137. Kim, D. et al. Optimizing methods and dodging pitfalls in microbiome research. Microbiome 5, 52 (2017).

    PubMed  PubMed Central  Google Scholar 

  138. Panek, M. et al. Methodology challenges in studying human gut microbiota — effects of collection, storage, DNA extraction and next generation sequencing technologies. Sci. Rep. 8, 2045–2322 (2018).

    Google Scholar 

  139. Holm, A. & Rune, A. Urine sampling techniques in symptomatic primary-care patients: a diagnostic accuracy review. BMC Fam. Pract. 17, 72 (2016).

    PubMed  PubMed Central  Google Scholar 

  140. Southworth, E. et al. A cross-sectional pilot cohort study comparing standard urine collection to the Peezy midstream device for research studies involving women. Female Pelv. Med. Reconstr. Surg. 25, e28–e33 (2019).

    Google Scholar 

  141. Łusiak-Szelachowska, M., Weber-Dabrowska, B., Jonczyk-Matysiak, E., Wojciechowska, R. & Górski, A. Bacteriophages in the gastrointestinal tract and their implications. Gut Pathog. 9, 44 (2017).

    PubMed  PubMed Central  Google Scholar 

  142. Barr, J. J. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl Acad. Sci. USA 110, 10771–10776 (2013).

    CAS  PubMed  Google Scholar 

  143. Shan, J. et al. Bacteriophages are more virulent to bacteria with human cells than they are in bacterial culture; insights from HT-29 cells. Sci. Rep. 8, 5091 (2018).

    PubMed  PubMed Central  Google Scholar 

  144. Dabrowska, K. et al. Antitumor activity of bacteriophages in murine experimental cancer models caused possibly by inhibition of beta3 integrin signaling pathway. Acta Virol. 48, 241–248 (2004).

    CAS  PubMed  Google Scholar 

  145. Duerkop, B. A. & Hooper, L. V. Resident viruses and their interactions with the immune system. Nat. Immunol. 14, 654–659 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Nieth, A., Verseux, C. & Römer, W. A. Question of attire: dressing up bacteriophage therapy for the battle against antibiotic-resistant intracellular bacteria. Springer Sci. Rev. 3, 1–11 (2015).

    Google Scholar 

  147. Zhang, L. et al. Intracellular Staphylococcus aureus control by virulent bacteriophages within MAC-T bovine mammary epithelial cells. Antimicrob. Agents Chemother. 61, e01990–16 (2017).

    Google Scholar 

  148. Górski, A. et al. Phages and immunomodulation. Future Microbiol. 12, 905–914 (2017).

    PubMed  Google Scholar 

  149. Górski, A. et al. Bacteriophages and transplantation tolerance. Transplant. Proc. 38, 331–333 (2006).

    PubMed  Google Scholar 

  150. Dabrowska, K. et al. Immunogenicity studies of proteins forming the T4 phage head surface. J. Virol. 88, 12551–12557 (2014).

    PubMed  PubMed Central  Google Scholar 

  151. Tothova, L. et al. Phage therapy of Cronobacter-induced urinary tract infection in mice. Med. Sci. Monit. 17, BR173–BR178 (2011).

    PubMed  PubMed Central  Google Scholar 

  152. Duerkop, B. A., Clements, C. V., Rollins, D., Rodrigues, J. L. M. & Hooper, L. V. A composite bacteriophage alters colonization by an intestinal commensal bacterium. Proc. Natl Acad. Sci. USA 109, 17621–17626 (2012).

    CAS  PubMed  Google Scholar 

  153. Gama, J. A. et al. Temperate bacterial viruses as double-edged swords in bacterial warfare. PLOS ONE 8, e59043 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Lin, D. M., Koskella, B. & Lin, H. C. Phage therapy: an alternative to antibiotics in the age of multi-drug resistance. World J. Gastrointest. Pharmacol. Ther. 8, 162 (2017).

    PubMed  PubMed Central  Google Scholar 

  155. Caldwell, J. A. Bacteriophagy in urinary infections following the administration of the bacteriophage therapeutically. Arch. Intern. Med. 41, 189 (1928).

    Google Scholar 

  156. Gill, G. & Young, R. F. in Emerging Trends in Antibacterial Discovery (eds Miller, A. A. & Miller, P. F.) 367–407 (Caister Academic Press, 2011).

  157. Sybesma, W. et al. Bacteriophages as potential treatment for urinary tract infections. Front. Microbiol. 7, 465 (2016).

    PubMed  PubMed Central  Google Scholar 

  158. Khawaldeh, A. et al. Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J. Med. Microbiol. 60, 1697–1700 (2011).

    CAS  PubMed  Google Scholar 

  159. Leitner, L. et al. Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urol. 17, 90 (2017).

    PubMed  PubMed Central  Google Scholar 

  160. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03140085 (2017).

  161. Ujmajuridze, A. et al. Adapted bacteriophages for treating urinary tract infections. Front. Microbiol. 9, 1832 (2018).

    PubMed  PubMed Central  Google Scholar 

  162. Siddiq, D. M. & Darouiche, R. O. New strategies to prevent catheter-associated urinary tract infections. Nat. Rev. Urol. 9, 305–314 (2012).

    CAS  PubMed  Google Scholar 

  163. Fu, W. et al. Bacteriophage cocktail for the prevention of biofilm formation by Pseudomonas aeruginosa on catheters in an in vitro model system. Antimicrob. Agents Chemother. 54, 397–404 (2010).

    CAS  PubMed  Google Scholar 

  164. Melo, L. D. R. et al. Development of a phage cocktail to control Proteus mirabilis catheter-associated urinary tract infections. Front. Microbiol. 7, 1024 (2016).

    PubMed  PubMed Central  Google Scholar 

  165. Liao, K. S., Lehman, S. M., Tweardy, D. J., Donlan, R. M. & Trautner, B. W. Bacteriophages are synergistic with bacterial interference for the prevention of Pseudomonas aeruginosa biofilm formation on urinary catheters. J. Appl. Microbiol. 113, 1530–1539 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Abedon, S. T., Kuhl, S. J., Blasdel, B. G. & Kutter, E. M. Phage treatment of human infections. Bacteriophage 1, 66–85 (2011).

    PubMed  PubMed Central  Google Scholar 

  167. Schooley, R. T. et al. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob. Agents Chemother. 61, e00954–17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Chan, B. K. et al. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol. Med. Public Health 2018, 60–66 (2018).

    PubMed  PubMed Central  Google Scholar 

  169. Sirha, N. et al. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat. Rev. Urol. 15, 750–776 (2018).

    Google Scholar 

  170. Nobrega, F. L. et al. Targeting mechanisms of tailed bacteriophages. Nat. Rev. Microbiol. 16, 760–773 (2018).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the NIH (R01 DK104718 to A.J.W.). A.G. is supported by the Carbon Research Fellowship at Loyola University Chicago. T.M.-E. was supported by a Loyola University Chicago Interdisciplinary Research Fellowship. The authors thank J. Shapiro for critical reading of the manuscript and assistance with generating the transmission electron microscopy image.

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Nature Reviews Urology thanks A. Górski and other anonymous reviewer(s) for their contribution to the peer review of this work.

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A.G. and T.M.-E. researched data for the article. All authors made substantial contribution to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Catherine Putonti.

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Garretto, A., Miller-Ensminger, T., Wolfe, A.J. et al. Bacteriophages of the lower urinary tract. Nat Rev Urol 16, 422–432 (2019). https://doi.org/10.1038/s41585-019-0192-4

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