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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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Updates in Clinical Management of Recurrent Urinary Tract Infections
Siddiqui, N. Y., & Bradley, M. S. (2025) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000006060 · Cited by 12
Lee, S., Choe, H., Na, Y. G., Kim, K. H., Kim, J. H., Chung, H., Chung, J. M., Jung, J. H., Choi, H., Lee, S., et al. (2017) · Urogenital Tract Infection · doi:10.14777/uti.2017.12.1.7 · Cited by 12
Collins, L., Sathiananthamoorthy, S., Rohn, J. L., & Malone‐Lee, J. (2020) · International Urogynecology Journal · doi:10.1007/s00192-020-04272-x · Cited by 12
Metformin strengthens uroepithelial immunity against E. coli infection
Majhi, R. K., Mohanty, S., Kamolvit, W., White, J. K., Scheffschick, A., Brauner, H., & Brauner, A. (2021) · Scientific Reports · doi:10.1038/s41598-021-98223-1 · Cited by 12
The unexplored relationship between urinary tract infections and the autonomic nervous system
Hibbing, M. E., Conover, M. S., & Hultgren, S. J. (2015) · Autonomic Neuroscience · doi:10.1016/j.autneu.2015.06.002 · Cited by 12
“Evidence of IBCs and bacterial filaments have been observed in women suffering acute UTI, 1 to 2 days post-self-reported sexual intercourse, but not in healthy controls or infections caused by non-IBC forming Gram-positive organisms (Rosen et al., 2007).”
Self-citationPathoadaptive Mutations in Uropathogenic Escherichia coli
Sokurenko, E. V. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.uti-0020-2015 · Cited by 13
Fluoroquinolone resistance during 2000–2005 : An observational study
Ryan, R. J., Lindsell, C. J., & Sheehan, P. (2008) · BMC Infectious Diseases · doi:10.1186/1471-2334-8-71 · Cited by 12
“Biofilms have been demonstrated to markedly increase needed minimum inhibitory concentrations (MICs) and a recent study by Rosen et al found filamentous bacteria were common even in healthy women with uncomplicated cystitis [11].”
Uropathogenic Escherichia coli biofilms
Nhu, N. T. K., Ravi, C., & Schembri, M. A. (2023) · Microbiology Australia · doi:10.1071/ma23030 · Cited by 11
Multispecies bacterial invasion of human host cells
Abell-King, C., Pokhrel, A., Rice, S. A., Duggin, I. G., & Söderström, B. (2024) · Pathogens and Disease · doi:10.1093/femspd/ftae012 · Cited by 11
“These morphologies were later also seen in female patents with cystitis (Rosen et al. 2007 ) and mor e r ecentl y also confirmed in flow-c hamber models using human bladder cells and urine (Andersen et al. 2012 , Klein et al. 2015 , Iosifidis and Duggin 2020 , Söderström et al. 2022 ).”
Young, M., Straub, T. J., Worby, C. J., Metsky, H. C., Gnirke, A., Bronson, R. A., van Dijk, L. R., Desjardins, C. A., Matranga, C. B., Qu, J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53829-7 · Cited by 12
“Although we focused on E. coli within the gut, broader applications of E. coli PanSelect include the detection of low-abundance strains across other environments such as the skin 64 , catheter, bladder 7,65,66 , hospitals 67 and in the food industry 68 .”
Self-citationGonzález, M. J., Navarro, N., Cruz, E., Sánchez, S., Morales, J. O., Zunino, P., Robino, L., Lima, A. E., & Scavone, P. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1493859 · Cited by 11
Kelley, S. P., Courtneidge, H. R., Birch, R., Contreras‐Sanz, A., Kelly, M. C., Durodie, J., Peppiatt‐Wildman, C. M., Farmer, C., Delaney, M. P., Malone‐Lee, J., et al. (2014) · SpringerPlus · doi:10.1186/2193-1801-3-200 · Cited by 11
“We find 44% of our RTR cohort to have intracellular bacteria, whereas Rosen et al. found intracellular bacteria in just 18% of their UTI cohort (Rosen et al. 2007).”
BackgroundUrinary Tract Infections in Children
Montini, G., Spencer, J. D., & Hewitt, I. K. (2021) · Springer eBooks · doi:10.1007/978-3-642-27843-3_49-2 · Cited by 11
Proteomic analysis of uropathogenicEscherichia coli
Cash, P. (2014) · Expert Review of Proteomics · doi:10.1586/14789450.2014.877845 · Cited by 11
“coli forms an IBC within the cells of the urinary tract epithelium, thus forming the bacterial reservoir in chronic infections [136].”
BackgroundIn Vitro Effects of Homeopathic Drugs on Cultured Escherichia coli
Kurmann, C., Imbach, E., Amsler, F., Pannek-Rademacher, S., & Pannek, J. (2018) · Homeopathy · doi:10.1055/s-0038-1637729 · Cited by 12
Yu, Y., Singh, H., Tsitrin, T., Bekele, S., Lin, Y.-H., Sikorski, P. M., Moncera, K. J., Torralba, M., Morrow, L. E., Wolcott, R. D., et al. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.667462 · Cited by 13
“coli strains causing recurrent UTI (45, 46).”
Amoura, A., Pistien, C., Chaligne, C., Dion, S., Magnan, M., Bridier‐Nahmias, A., Baron, A., Chau, F., Bourgogne, E., Lê, M., et al. (2024) · Cell Host & Microbe · doi:10.1016/j.chom.2024.04.015 · Cited by 12
Stærk, K., Grønnemose, R. B., Palarasah, Y., Lund, L. C., & Andersen, T. E. (2022) · Microbial Pathogenesis · doi:10.1016/j.micpath.2022.105817 · Cited by 10
“Although bacterial filaments are absent in most urine samples from human UTI patients, they have been occasionally observed [19].”
BackgroundBilsen, M. P., van Uhm, J. I. M., Stalenhoef, J. E., van Nieuwkoop, C., Groenwold, R. H. H., Visser, L. G., & Lambregts, M. M. C. (2023) · JAC-Antimicrobial Resistance · doi:10.1093/jacamr/dlad040 · Cited by 10
Gunathilaka, G. A. D. K. K., Dewasmika, W. A. P. M., Sandaruwan, U. M., Neelawala, N. G. A. K., Madhumali, G. E. D., Dissanayake, B. N., Priyantha, M. A. R., Prasada, D. V. P., & Dissanayake, D. R. A. (2024) · Comparative Immunology Microbiology and Infectious Diseases · doi:10.1016/j.cimid.2023.102123 · Cited by 10
Demirel, I., Kruse, R. L., Önnberg, A., & Persson, K. (2014) · Microbial Pathogenesis · doi:10.1016/j.micpath.2014.11.015 · Cited by 10
“pneumoniae and Proteus mirabilis have been observed inmurine UTI-models [19] and in urine fromwomenwith UTI [17].”
BackgroundA 9-year audit of the efficacy of diathermy for cystitis cystica
Chen, Z., Bates, L. J., West, N. T., & Moore, K. H. (2019) · Urogynaecologia · doi:10.4081/uij.2019.223 · Cited by 10
Ognenovska, S., Mukerjee, C., Sanderson‐Smith, M. L., Moore, K. H., & Mansfield, K. J. (2022) · Pathogens · doi:10.3390/pathogens11080926 · Cited by 10
Filippini, M., Ortelli, C., Švercel, M., & Bagheri, H. C. (2011) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2011.03.018 · Cited by 10
Communal Living by Bacteria and the Pathogenesis of Urinary Tract Infections
Opal, S. M. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040349 · Cited by 10
“Rosen and colleagues [1] now go one step further, showing that intracellular communities of gram-negative bacteria are a widespread finding even in uncomplicated lower urinary tract infections (UTIs).”
BackgroundRecurrent Urinary Tract Infections (UTIs): A Review and Proposal for Clinicians
Sgarabotto, D., Andretta, E., & Sgarabotto, C. (2025) · Antibiotics · doi:10.3390/antibiotics14010022 · Cited by 9
Nur77 protects the bladder urothelium from intracellular bacterial infection
Collins, C. A., Waller, C., Batourina, E., Kumar, L., Mendelsohn, C. L., & Gilbert, N. M. (2024) · Nature Communications · doi:10.1038/s41467-024-52454-8 · Cited by 9
What is chronic urinary tract infection? A systematic review
Hjelmager, J. S., Andersen, K., Andersen, T. E., & Stærk, K. (2025) · British Journal of Urology · doi:10.1111/bju.16764 · Cited by 9
“Currently, however, the causal relation between intracellular reservoirs and recurrent UTI has not been convincingly demonstrated in humans [17].”
InfluentialChen, Z., Ognenovska, S., Sluyter, R., Moore, K. H., & Mansfield, K. J. (2021) · PLoS ONE · doi:10.1371/journal.pone.0247861 · Cited by 9
Urinary Tract Infections and the Mucosal Immune System
Ambite, I., Lutay, N., Godaly, G., & Svanborg, C. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-415847-4.00106-3 · Cited by 9
Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections
Cusumano, Z., Klein, R. D., & Hultgren, S. J. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.vmbf-0023-2015 · Cited by 10
“The culmination of this work has led to the development of small, orally bioavailable compounds capable of preventing acute UTIs and treating chronic UTIs (188).”
InfluentialSelf-citationRecurrent urinary tract infections in adults: a practical guide
Hughes, T., Juliebø‐Jones, P., Saada, L., Saeed, K. B. A., & Somani, B. K. (2021) · British Journal of Hospital Medicine · doi:10.12968/hmed.2021.0337 · Cited by 9
Invasion of Host Cells and Tissues by Uropathogenic Bacteria
Lewis, A. J., Richards, A. C., & Mulvey, M. A. (2016) · ASM Press eBooks · doi:10.1128/9781555817404.ch16 · Cited by 8
Aurantiogliocladin inhibits biofilm formation at subtoxic concentrations
Yuyama, K. T., Neves, T. S. P. D. C., Memória, M. T., Tartuci, I. T., & Abraham, W. (2017) · AIMS Microbiology · doi:10.3934/microbiol.2017.1.50 · Cited by 9
“in the cystic fibrosis lung [2], the middle ear [3], the urinary tract [4] or gastric mucosa [5].”
BackgroundBlanc, L. L., Alric, B., Rollin, R., Xénard, L., Finn, L. R., Goussard, S., Mazenq, L., Ingersoll, M. A., Piel, M., Tinévez, J.-Y., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.20.614086 · Cited by 9
“For example, uropathogenic Escherichia coli ( E. coli ) invade cells of the bladder epithelium forming dense intracellular bacterial communities (IBCs)( 21 , 22 ).”
Robinson, C. K., Saenkham, P., Hanson, B. S., Adams, L. G., & Subashchandrabose, S. (2022) · Infection and Immunity · doi:10.1128/iai.00532-21 · Cited by 8
Kuprasertkul, A., Gadhvi, J. G., Fuentes, J. L., Khan, F., Neugent, M. L., Nisco, N. J. D., & Zimmern, P. E. (2022) · World Journal of Urology · doi:10.1007/s00345-022-04050-y · Cited by 8
“This procedure targets bacterial reservoirs previously demonstrated to remain in the bladder wall after bacteriuria resolved in both mouse models and human RUTI patients [13, 14].”
BackgroundDauros‐Singorenko, P., & Swift, S. (2014) · Science Progress · doi:10.3184/003685014x14151846374739 · Cited by 8
Tamadonfar, K. O., Omattage, N. S., Spaulding, C. N., & Hultgren, S. J. (2020) · John Wiley & Sons, Inc. eBooks · doi:10.1128/9781683670261.ch6 · Cited by 8
Self-citationChen, Z., Moore, K. H., Mansfield, K. J., Ognenovska, S., Allen, W., Parkin, K., Mukerjee, C., Aryal, N. R., & Gebski, V. (2020) · Neurourology and Urodynamics · doi:10.1002/nau.24525 · Cited by 8
“Urothelial cells exfoliated from women with acute UTI and DO have been found to contain intracellular bacteria.(7,8) Similarly, the polymerase chain reaction of urine from patients with refractory DO and recurrent UTI revealed high bacterial diversity.”
ResultMartín-Gutiérrez, G., Docobo-Pérez, F., Rodríguez-Martínez, J. M., Pascual, Á., Blázquez, J., & Rodríguez-Beltrán, J. (2020) · Antibiotics · doi:10.3390/antibiotics9110802 · Cited by 8
“coli cells into the bladder lumen [16] and leading to the liberation of intracellular molecules such as G6P.”
BackgroundSchlager, T. A., Hendley, J. O., & Peters, C. A. (2009) · The Journal of Urology · doi:10.1016/j.juro.2009.02.063 · Cited by 8
Nosocomial Urinary Tract Infections
Hooton, T. M. (2010) · Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases · doi:10.1016/b978-0-443-06839-3.00304-0 · Cited by 8
Self-citation
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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