Flores, Carlos; Ling, Jefferson; Loh, Amanda; Maset, Ramón G; Aw, Angeline; White, Ian J; Fernando, Raymond; Flores, Carlos; Ling, Jefferson; Loh, Amanda; Maset, Ramón G; Aw, Angeline; White, Ian J; Fernando, Raymond; Rohn, Jennifer L; - view fewer (2023) A human urothelial microtissue model reveals shared colonization and survival strategies between uropathogens and commensals. Science Advances , 9 (45) , Article eadi9834. 10.1126/sciadv.adi9834.

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Abstract

Urinary tract infection is among the most common infections worldwide, typically studied in animals and cell lines with limited uropathogenic strains. Here, we assessed diverse bacterial species in a human urothelial microtissue model exhibiting full stratification, differentiation, innate epithelial responses, and urine tolerance. Several uropathogens invaded intracellularly, but also commensal Escherichia coli, suggesting that invasion is a shared survival strategy, not solely a virulence hallmark. The E. coli adhesin FimH was required for intracellular bacterial community formation, but not for invasion. Other shared lifestyles included filamentation (Gram-negatives), chaining (Gram-positives), and hijacking of exfoliating cells, while biofilm-like aggregates were formed mainly with Pseudomonas and Proteus. Urothelial cells expelled invasive bacteria in Rab-/LC3-decorated structures, while highly cytotoxic/invasive uropathogens, but not commensals, disrupted host barrier function and strongly induced exfoliation and cytokine production. Overall, this work highlights diverse species-/strain-specific infection strategies and corresponding host responses in a human urothelial microenvironment, providing insights at the microtissue, cell, and molecular level.

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