Transient microbiota exposures activate dormant <i>Escherichia coli</i> infection in the bladder and drive severe outcomes of recurrent disease

<div><p>Pathogens often inhabit the body asymptomatically, emerging to cause disease in response to unknown triggers. In the bladder, latent intracellular <i>Escherichia coli</i> reservoirs are regarded as likely origins of recurrent urinary tract infection (rUTI), a problem affecting millions of women worldwide. However, clinically plausible triggers that activate these reservoirs are unknown. Clinical studies suggest that the composition of a woman’s vaginal microbiota influences her susceptibility to rUTI, but the mechanisms behind these associations are unclear. Several lines of evidence suggest that the urinary tract is routinely exposed to vaginal bacteria, including <i>Gardnerella vaginalis</i>, a dominant member of the vaginal microbiota in some women. Using a mouse model, we show that bladder exposure to <i>G</i>. <i>vaginalis</i> triggers <i>E</i>. <i>coli</i> egress from latent bladder reservoirs and enhances the potential for life-threatening outcomes of the resulting <i>E</i>. <i>coli</i> rUTI. Transient <i>G</i>. <i>vaginalis</i> exposures were sufficient to cause bladder epithelial apoptosis and exfoliation and interleukin-1-receptor-mediated kidney injury, which persisted after <i>G</i>. <i>vaginalis</i> clearance from the urinary tract. These results support a broader view of UTI pathogenesis in which disease can be driven by short-lived but powerful urinary tract exposures to vaginal bacteria that are themselves not “uropathogenic” in the classic sense. This “covert pathogenesis” paradigm may apply to other latent infections, (e.g., tuberculosis), or for diseases currently defined as noninfectious because routine culture fails to detect microbes of recognized significance.</p>