GSE117532
Host susceptibility to recurrent cystitis is shaped by bladder TNF-alpha signaling dynamics
Urinary tract infections (UTI) are common and recurrent. Both host genetics and UTI history impact susceptibility to recurrent UTI (rUTI) in women and in animal models. To identify shared patterns of host response that correlate with susceptibility, we investigated bladder inflammatory and transcriptional kinetics in acute and rUTI models. We found that TNF? signaling kinetics differed with mouse strain and infection history. Mice resistant to severe UTI/rUTI displayed a robust TNF?-dependent inflammation during the first 6 hours of acute cystitis, which waned by 24 hours; mice that are susceptible varied in their early responses but were prone to severe inflammation at 24 hours post-infection. Depletion of TNF? in an rUTI model revealed that early TNF? signaling promoted colonization resistance via exfoliation of infected bladder cells, but prolonged TNF? signaling exacerbated inflammation, thereby worsening infection. Host genetics and disease history impacts susceptibility by regulating the kinetics of a common TNF? pathway. Overall design: Whole bladder transcritpomes of mice from different genetic background or of different UTI histories were compared upon UPEC infection for different period of time with PBS mock infected counterparts.