Dynamic persistence of UPEC intracellular bacterial communities in a human bladder-chip model of urinary tract infection
- Swiss Federal Institute of Technology in Lausanne (EPFL), Switzerland
Abstract
Uropathogenic Escherichia coli (UPEC) proliferate within superficial bladder umbrella cells to form intracellular bacterial communities (IBCs) during early stages of urinary tract infections. However, the dynamic responses of IBCs to host stresses and antibiotic therapy are difficult to assess in situ. We develop a human bladder-chip model wherein umbrella cells and bladder microvascular endothelial cells are co-cultured under flow in urine and nutritive media respectively, and bladder filling and voiding mimicked mechanically by application and release of linear strain. Using time-lapse microscopy, we show that rapid recruitment of neutrophils from the vascular channel to sites of infection leads to swarm and neutrophil extracellular trap formation but does not prevent IBC formation. Subsequently, we tracked bacterial growth dynamics in individual IBCs through two cycles of antibiotic administration interspersed with recovery periods which revealed that the elimination of bacteria within IBCs by the antibiotic was delayed, and in some instances, did not occur at all. During the recovery period, rapid proliferation in a significant fraction of IBCs reseeded new foci of infection through bacterial shedding and host cell exfoliation. These insights reinforce a dynamic role for IBCs as harbours of bacterial persistence, with significant consequences for non-compliance with antibiotic regimens.
Data availability
Data generated in this study has been uploaded to the EPFL community page at Zenodo and is available at the following doi: 10.5281/zenodo.5028262
Article and author information
Author details
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030B_176397)
- John D McKinney
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (51NF40_180541)
- John D McKinney
Human Frontier Science Program (Long-Term Fellowship,LT000231/2016-L)
- Vivek V Thacker
European Molecular Biology Organization (Long-Term Fellowship,921-2015)
- Vivek V Thacker
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Fresh human blood was procured from anonymised donors via the Transfusion Interregionale CRS network based in Bern, Switzerland. Approval for this project was provided by the same organisation under project number P_257.
Copyright
© 2021, Sharma et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Dynamic persistence of UPEC intracellular bacterial communities in a human bladder-chip model of urinary tract infection
eLife 10:e66481.
https://doi.org/10.7554/eLife.66481
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