Urinary tract infections (UTIs) are among the most common bacterial infections, with over 400 million cases diagnosed globally each year. More than one-third fail to respond to current antibiotics, leading to recurrent or chronic infections. In children, progression to kidney infection (pyelonephritis) can cause irreversible renal scarring and lifelong kidney function impairment, predisposing to chronic kidney disease (CKD). New therapeutic strategies that prevent infection-induced CKD are urgently needed.
Using bulk RNA sequencing of the urinary bladder, we identified interleukin (IL)-33 as the most highly upregulated immune factor following UTI in mice. Functional studies revealed that IL-33 drives susceptibility to pyelonephritis and permanent kidney dysfunction. Single-cell RNA sequencing of urinary bladder immune cells demonstrated that the IL-33 receptor is predominantly expressed by group 2 innate lymphoid cells (ILC2s), identifying ILC2s as key downstream mediators of IL-33 signalling. Spatial RNA sequencing revealed basal urothelial stem cells as the primary source of IL-33, and three-dimensional confocal microscopy confirmed that IL-33⁺ basal cells and ILC2s are co-localised within the suburothelial niche. Both IL-33 expression and ILC2 numbers increased markedly following uropathogenic E. coli infection, suggesting the coordinated activation of this IL-33–ILC2 axis during UTI.
Finally, urinary IL-33 levels were elevated in patients with recurrent or chronic UTIs, with the highest levels observed in those with multidrug-resistant infections. Given that anti-IL-33 therapies are in late-stage clinical trials for severe respiratory diseases, these data provide proof-of-principle evidence to support repurposing anti-IL-33 immunotherapy to protect kidney health following severe UTI, particularly in children.