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Detection of Intracellular Bacterial Communities in Human Urinary Tract Infection
Open accessAbstract
BACKGROUND: Urinary tract infections (UTIs) are one of the most common bacterial infections and are predominantly caused by uropathogenic Escherichia coli (UPEC). While UTIs are typically considered extracellular infections, it has been recently demonstrated that UPEC bind to, invade, and replicate within the murine bladder urothelium to form intracellular bacterial communities (IBCs). These IBCs dissociate and bacteria flux out of bladder facet cells, some with filamentous morphology, and ultimately establish quiescent intracellular reservoirs that can seed recurrent infection. This IBC pathogenic cycle has not yet been investigated in humans. In this study we sought to determine whether evidence of an IBC pathway could be found in urine specimens from women with acute UTI. METHODS AND FINDINGS: We collected midstream, clean-catch urine specimens from 80 young healthy women with acute uncomplicated cystitis and 20 asymptomatic women with a history of UTI. Investigators were blinded to culture results and clinical history. Samples were analyzed by light microscopy, immunofluorescence, and electron microscopy for evidence of exfoliated IBCs and filamentous bacteria. Evidence of IBCs was found in 14 of 80 (18%) urines from women with UTI. Filamentous bacteria were found in 33 of 80 (41%) urines from women with UTI. None of the 20 urines from the asymptomatic comparative group showed evidence of IBCs or filaments. Filamentous bacteria were present in all 14 of the urines with IBCs compared to 19 (29%) of 66 samples with no evidence of IBCs (p < 0.001). Of 65 urines from patients with E. coli infections, 14 (22%) had evidence of IBCs and 29 (45%) had filamentous bacteria, while none of the gram-positive infections had IBCs or filamentous bacteria. CONCLUSIONS: The presence of exfoliated IBCs and filamentous bacteria in the urines of women with acute cystitis suggests that the IBC pathogenic pathway characterized in the murine model may occur in humans. The findings support the occurrence of an intracellular bacterial niche in some women with cystitis that may have important implications for UTI recurrence and treatment.
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“IBCs have long been reported in the urine of patients with acute cystitis; however, they have not been detected in the urine of patients with acute episodes of rUTIs [25].”
From Vaginal microbiota and urinary tract infections in women: the protective role of vaginal lactobacilli in counteracting urinary tract infections occurrence and recurrence (2026) · cites this paper as [25]
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Urinary tract infections and bacterial prostatitis in men
Wagenlehner, F. R. A., Weidner, W., Pilatz, A. M. E., & Naber, K. G. (2013) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0000000000000024 · Cited by 64
“This finding suggests that intracellular bacterial reservoirs may also play a role in humans [22].”
BackgroundWang, C., Symington, J., Ma, E., Cao, B., & Mysorekar, I. U. (2012) · Infection and Immunity · doi:10.1128/iai.01234-12 · Cited by 66
“anesthetized and inoculated, via transurethral catheterization, with 50 l of a bacterial suspension (10(7) CFU) of UTI89 in phosphate-buffered saline (PBS) as described previously (11, 13).”
BackgroundMethodRecurrent Uncomplicated Urinary Tract Infections in Women: A Review
Nosseir, S. B., Lind, L. R., & Winkler, H. A. (2011) · Journal of Women s Health · doi:10.1089/jwh.2011.3056 · Cited by 63
“Interestingly, small numbers of intracellular bacteria have been identified in exfoliated epithelial cells of women with acute cystitis.(15) It seems that small colonies of intracellular bacteria are able to evade antibiotic and immune mechanisms.”
Billips, B. K., Yaggie, R. E., Cashy, J., Schaeffer, A. J., & Klumpp, D. J. (2009) · The Journal of Infectious Diseases · doi:10.1086/599839 · Cited by 63
“urothelial cells by UPEC strains has been demonstrated in both animal models and human patients with UTI [22-25].”
ResultHyre, A. N., Kavanagh, K., Kock, N. D., Donati, G. L., & Subashchandrabose, S. (2016) · Infection and Immunity · doi:10.1128/iai.01041-16 · Cited by 67
“Free-living, adherent, biofilm, and intracellular forms of UPEC are found in the urinary bladder (5, 6).”
BackgroundReassessment of Routine Midstream Culture in Diagnosis of Urinary Tract Infection
Sathiananthamoorthy, S., Malone‐Lee, J., Gill, K., Tymon, A. M., Nguyen, T. K., Gurung, S., Collins, L., Kupelian, A., Swamy, S., Khasriya, R., et al. (2018) · Journal of Clinical Microbiology · doi:10.1128/jcm.01452-18 · Cited by 63
The urinary microbiome and biological therapeutics: Novel therapies for urinary tract infections
Kenneally, C., Murphy, C. P., Sleator, R. D., & Culligan, E. P. (2022) · Microbiological Research · doi:10.1016/j.micres.2022.127010 · Cited by 69
Balsara, Z. R., Ross, S. S., Dolber, P. C., Wiener, J. S., Tang, Y., & Seed, P. C. (2013) · Infection and Immunity · doi:10.1128/iai.00255-13 · Cited by 59
The arsenal of pathogens and antivirulence therapeutic strategies for disarming them
Hadjifrangiskou, M., & Brannon, J. R. (2016) · Drug Design Development and Therapy · doi:10.2147/dddt.s98939 · Cited by 58
“136 The 137–139 Furthermore, the presence of QIR in human UPEC UTIs validates AVTs, targeting this critical step in pathogenesis.”
Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections
O'Brien, V. P., Hannan, T. J., Nielsen, H. V., & Hultgren, S. J. (2016) · ASM Press eBooks · doi:10.1128/9781555817404.ch24 · Cited by 59
Self-citationUpdate on Childhood Urinary Tract Infection and Vesicoureteral Reflux
Bell, L. E., & Mattoo, T. K. (2009) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2009.03.011 · Cited by 58
A Murine Model for Escherichia coli Urinary Tract Infection
Hannan, T. J., & Hunstad, D. A. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2854-5_14 · Cited by 58
“Finally, the relevance of the murine IBC cascade to human cystitis is corroborated by the identification of filamentous UPEC (and other Gram-negative uropathogens) and exfoliated, IBC-bearing uroepithelial cells in the urine of patients with UTI [39, 40].”
BackgroundKinetics of Uropathogenic Escherichia coli Metapopulation Movement during Urinary Tract Infection
Walters, M. S., Lane, M. C., Vigil, P. D., Smith, S. N., Walk, S. T., & Mobley, H. L. T. (2012) · mBio · doi:10.1128/mbio.00303-11 · Cited by 58
“While in the bladder, UPEC is capable of invading the cytoplasm of superficial facet cells and creating clusters of rapidly growing bacteria termed intracellular bacterial communities (IBCs) (13, 14).”
BackgroundDamX Controls Reversible Cell Morphology Switching in Uropathogenic Escherichia coli
Khandige, S., Asferg, C. A., Rasmussen, K. J., Larsen, M. J., Overgaard, M., Andersen, T. E., & Møller‐Jensen, J. (2016) · mBio · doi:10.1128/mbio.00642-16 · Cited by 57
Demirel, I., Persson, A., Brauner, A., Särndahl, E., Kruse, R. L., & Persson, K. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00081 · Cited by 57
“Several studies have shown that UPEC can invade, replicate and form intracellular bacterial communities in bladder epithelial cells and that the majority of clinical UPEC isolates have this ability (Rosen et al., 2007; Hannan et al., 2012).”
BackgroundLeatham-Jensen, M. P., Mokszycki, M. E., Rowley, D. C., Deering, R. W., Camberg, J. L., Sokurenko, E. V., Tchesnokova, V. L., Frimodt-Møller, J., Krogfelt, K. A., Nielsen, K. L., et al. (2016) · mSphere · doi:10.1128/msphere.00055-15 · Cited by 56
“Although the causes of recurrent UTI are complex (6), it appears that UPEC can bind to, enter, and replicate within superficial facet cells in the human and mouse bladder epithelium, resulting in intracellular biofilmlike communities (IBCs) (6, 7).”
Dikshit, N., Bist, P., Fenlon, S. N., Pulloor, N. K., Chua, C. E. L., Scidmore, M. A., Carlyon, J. A., Tang, B. L., Chen, S. L., & Sukumaran, B. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005083 · Cited by 58
SOS regulatory elements are essential for UPEC pathogenesis
Li, B., Smith, P. A., Horvath, D. J., Romesberg, F. E., & Justice, S. S. (2010) · Microbes and Infection · doi:10.1016/j.micinf.2010.04.009 · Cited by 53
“Whereas previously seen only in mouse bladders and urine, IBCs and filamentous bacteria have been identified in human urine samples and biopsies of patients infected with UPEC and Klebsiella pneumoniae [7,8], demonstrating clearly that these events occur as part of the human condition for multiple uropathogens.”
BackgroundDiagnosing inflammation and infection in the urinary system via proteomics
Yu, Y., Sikorski, P. M., Bowman-Gholston, C., Cacciabeve, N., Nelson, K. E., & Pieper, R. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-015-0475-3 · Cited by 53
“Methods: Innovative shotgun metaproteomic methods were used to analyze urine sediments from 120 patients also subjected to conventional urinalysis for various clinical reasons including suspected UTIs.”
BackgroundInfluentialJakobsen, L., Cattoir, V., Jensen, K. S., Hammerum, A. M., Nordmann, P., & Frimodt‐Møller, N. (2012) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dks224 · Cited by 53
Bolton, M. T., Horvath, D. J., Li, B., Cortado, H. H., Newsom, D. E., White, P., Partida‐Sánchez, S., & Justice, S. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033897 · Cited by 52
“Infection/Bacterial Strains UTI89/pANT4 [43,54], a prototypical UPEC strain obtained from a patient with cystitis [35] which contains an episomal plasmid asserting ampicillin resistance, was used for all studies.”
BackgroundInfluentialUrinary Tract Infections in Adults
Hooton, T. M. (2010) · Elsevier eBooks · doi:10.1016/b978-0-323-05876-6.00051-4 · Cited by 52
Self-citationPeñaranda, C., Chumbler, N. M., & Hung, D. T. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009534 · Cited by 52
“QIRs are more prevalent in Balb/c compared to C57BL/6 mice demonstrating host variability in the resolution of UTIs [61].”
BackgroundInfluentialDadswell, K., Creagh, S., McCullagh, E., Liang, M., Brown, I. R., Warren, M. J., McNally, A., MacSharry, J. A., & Prentice, M. B. (2019) · Infection and Immunity · doi:10.1128/iai.00211-19 · Cited by 52
“coli urinary tract infection, rapid invasion of bladder cells occurs with the formation of intracellular bacterial communities (IBCs) with biofilm-like properties, which initiate the infective process (9, 10).”
BackgroundRobertson, P., Abdelhady, H., & Garduño, R. A. (2014) · Frontiers in Microbiology · doi:10.3389/fmicb.2014.00670 · Cited by 51
“Key to the decision of including a discussion on VBNC Lp as a distinct developmental form, was to take a side on the controversy of whether the VBNC state results from differentiation or simply from cell injury (Nyström, 2003).”
BackgroundInnate Immune Responses to Bladder Infection
Hayes, B. W., & Abraham, S. N. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.uti-0024-2016 · Cited by 53
Chen, Z., Phan, M., Bates, L. J., Peters, K. M., Mukerjee, C., Moore, K. H., & Schembri, M. A. (2018) · International Urogynecology Journal · doi:10.1007/s00192-018-3679-2 · Cited by 51
“Evidence for the existence of IBCs and quiescent bacteria has been reported in human patients [8, 16], supporting the possibility that the bladder could serve as a reservoir for rUTI.”
BackgroundO'Brien, V. P., Hannan, T. J., Schaeffer, A. J., & Hultgren, S. J. (2014) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0000000000000130 · Cited by 53
Self-citationElazar, S., Gonen, E., Livneh-Kol, A., Rosenshine, I., & Shpigel, N. Y. (2010) · Veterinary Research · doi:10.1051/vetres/2010025 · Cited by 49
“The relative MPO activity was calculated by the ratio between total MPO activity measured in the LPS-challenged gland and in the contralateral, unchallenged controlled gland.”
Mucosal infection rewires TNFɑ signaling dynamics to skew susceptibility to recurrence
Yu, L., O'Brien, V. P., Livny, J., Dorsey, D. A., Bandyopadhyay, N., Colonna, M., Caparon, M. G., Roberson, E. D. O., Hultgren, S. J., & Hannan, T. J. (2019) · eLife · doi:10.7554/elife.46677 · Cited by 49
Self-citationEstablishment and Characterization of UTI and CAUTI in a Mouse Model
Conover, M. S., Flores‐Mireles, A. L., Hibbing, M. E., Dodson, K., & Hultgren, S. J. (2015) · Journal of Visualized Experiments · doi:10.3791/52892 · Cited by 53
Self-citationZhang, L., Huang, W., Zhang, S., Li, Q., Wang, Y., Chen, T., Jiang, H., Kong, D., Lv, Q., Zheng, Y., et al. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.858777 · Cited by 48
“In severe cases, infection can spread to the kidneys, invade the bloodstream, and cause uremia and bacteremia (Rosen et al., 2007; Schmidt et al., 2017; Neugent et al., 2020; Kaushik et al., 2021).”
BackgroundSaldaña‐Ahuactzi, Z., la Cruz, M. Á. D., Carrillo-Casas, E. M., Durán, L., Zhang, Y., Hernández‐Castro, R., Puente, J. L., Daaka, Y., & Girón, J. A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101200 · Cited by 48
“Whereas previously seen only in mouse bladders and urine, these stages have been identified in human urine samples and human biopsies [12], demonstrating clearly that these events do occur as part of the human condition.”
BackgroundUropathogenic E. coli Exploit CEA to Promote Colonization of the Urogenital Tract Mucosa
Muenzner, P., Kengmo-Tchoupa, A., Klauser, B., Brunner, T., Putze, J., Dobrindt, U., & Hauck, C. R. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005608 · Cited by 40
“Detachment of the large superficial urothelial cells, which seems to be accompanied by apoptosis, then affords the pathogen access to deeper strata of the bladder epithelium, where some bacteria invade, multiply, and persist in undifferentiated epithelial cells [31,32].”
Modern diagnostic methods for urinary tract infections
Fritzenwanker, M., Imirzalioglu, C., Chakraborty, T., & Wagenlehner, F. R. A. (2016) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2016.1236685 · Cited by 48
The importance of intracellular bacterial biofilm in infectious diseases
Mirzaei, R., Mohammadzadeh, R., Sholeh, M., Karampoor, S., Abdi, M., Doğan, E., Moghadam, M. S., Kazemi, S., Jalalifar, S., Dalir, A., et al. (2020) · Microbial Pathogenesis · doi:10.1016/j.micpath.2020.104393 · Cited by 48
Clinical Presentations and Epidemiology of Urinary Tract Infections
Geerlings, S. E. (2016) · ASM Press eBooks · doi:10.1128/9781555817404.ch2 · Cited by 48
Applications of bacteriophages against intracellular bacteria
Śliwka, P., Ochocka, M., & Skaradzińska, A. (2021) · Critical reviews in microbiology · doi:10.1080/1040841x.2021.1960481 · Cited by 36
“It was observed in both mouse and human experiments that after breaking into the host cell cytosol, followed by intensive growth, UTI-associated bacteria form biofilm communities in which they reside for an extended period (Anderson et al. 2003; Rosen et al. 2007).”
BackgroundIntrahost Genome Alterations in Enterohemorrhagic Escherichia coli
Mellmann, A., Bielaszewska, M., & Karch, H. (2009) · Gastroenterology · doi:10.1053/j.gastro.2008.12.072 · Cited by 46
Bacterial differentiation, development, and disease: mechanisms for survival
Justice, S. S., Harrison, A., Becknell, B., & Mason, K. M. (2014) · FEMS Microbiology Letters · doi:10.1111/1574-6968.12602 · Cited by 46
Kostakioti, M., Hadjifrangiskou, M., Cusumano, C. K., Hannan, T. J., Janetka, J. W., & Hultgren, S. J. (2012) · Infection and Immunity · doi:10.1128/iai.00283-12 · Cited by 46
“The IBC pathogenic cascade, which has been characterized in a murine model of infection (2, 27, 29) and has been extensively documented in samples from human clinical studies (17, 42), is FimH dependent (52).”
BackgroundSelf-citationArreguin-Campos, R., Eersels, K., Lowdon, J. W., Rogosic, R., Heidt, B., Caldara, M., Jiménez-Monroy, K. L., Diliën, H., Cleij, T. J., & van Grinsven, B. (2021) · Microchemical Journal · doi:10.1016/j.microc.2021.106554 · Cited by 46
Antibiotherapy and pathogenesis of uncomplicated UTI: difficult relationships
Moura, A., Nicolau, A., Hooton, T. M., & Azeredo, J. (2009) · Journal of Applied Microbiology · doi:10.1111/j.1365-2672.2008.04115.x · Cited by 45
“The IBC cascade has not been demonstrated in humans, but a recently published paper demonstrates evidence of IBClike structures in exfoliated uroepithelial cells of women with acute cystitis (Rosen et al. 2007).”
BackgroundSelf-citationPutrinš, M., Kogermann, K., Lukk, E., Lippus, M., Varik, V., & Tenson, T. (2015) · Infection and Immunity · doi:10.1128/iai.02725-14 · Cited by 45
“In UPEC, it has been previously shown that recurrent communityacquired urinary tract infections are mainly due to persisting UPEC clones (22) and the presence of intracellular bladder reservoirs for UPEC in humans (23).”
BackgroundRowe, M. C., Withers, H. L., & Swift, S. (2010) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2010.01968.x · Cited by 46
“The understanding of recurrent UPEC UTIs has made significant advances in recent years with the discovery of intracellular bacterial (or biofilm-like) communities (IBCs) and quiescent intracellular reservoirs (QIRs) (Rosen et al., 2007; Wiles et al., 2008).”
Background
Metadata
- Authors
- Rosen, D. A., Hooton, T. M., Stamm, W. E., Humphrey, P. A., & Hultgren, S. J.
- Affiliations
- Washington University in St. Louis (US)
- University of Miami (US)
- University of Washington (US)
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2007-12-18
- Volume
- 4
- Issue
- 12
- Pages
- e329
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC2140087
- OpenAlex
- W2118051267
- Cited by
- 651
- References
- 31
- Citations by year
- 2026: 28 · 2025: 33 · 2024: 40 · 2023: 35 · 2022: 35 · 2021: 41 · 2020: 36 · 2019: 36 · 2018: 23 · 2017: 42 · 2016: 55 · 2015: 37 · 2014: 39 · 2013: 42 · 2012: 29
- FWCI
- 16.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Washington
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK053369, DK-53369, R01 DK64540, P50DK064540, DK051406, P01 DK53369, DK64540, R01DK051406)
- Office of Research on Women's Health
- Topics
- Health Sciences › Medicine › Urology › Urinary Tract Infections Management
- Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Keywords
- urinary tract infection, intracellular bacterial communities, uropathogenic Escherichia coli, acute uncomplicated cystitis, filamentous bacteria, recurrent urinary tract infection, women, bladder urothelium, human urine
- MeSH terms
- Acute Disease, Adult, Animals, Bacteria, Urinary Bladder, Cystitis, Disease Models, Animal, Escherichia coli Infections, Female, Fluorescent Antibody Technique, Humans, Mice, Inbred C3H, Microscopy, Electron, Scanning, Middle Aged, Recurrence, Urinary Tract Infections, Urine, Case-Control Studies, Urothelium, Mice
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