A Crohn’s Disease Susceptibility Gene, ATG16L1 Confers Protection From Urinary Tract Infections Caused By Uropathogenic Escherichia Coli In Mice And Humans

A polymorphism (T300A) in the ATG16L1 gene is associated with increased susceptibility to Crohn’s disease (CD). We identified a protective role of ATG16L1 deficiency in urinary tract infection (UTIs), very common recurrent infections caused predominantly by uropathogenic E. coli (UPEC). We posit that the protection to infectious disease might provide selective pressure on this CD risk allele. We demonstrate that ATG16L1 plays epithelial-intrinsic and macrophage-specific roles in UTI pathogenesis. Loss of ATG16L1 in epithelial cells results in reduction of persistent niches for UPEC and renders them unable to cause a recurrent UTI. Loss of ATG16L1 in macrophages enhances IL-1β release in response to UPEC, in a NOD2-independent but caspase-1/NLRP3 inflammasome-dependent manner. Inhibition of IL-1β signaling abrogates ATG16L1-dependent protection from UTIs. These phenotypes are replicated in mice carrying the T300A point mutation. Our work suggests that aberrant pro-inflammatory responses to commensals in the gut mucosa leading to CD pathogenesis may occur as a trade-off for productive responses to pathogens in the urinary tract mucosa. To extend our findings from mice to humans, we are conducting genomic studies to investigate associations between the T300A mutation and incidence of single and multiple UTIs and have found that presence of the T300A allele is associated with reduced incidence of UTIs in humans. Together, our findings have implications for elucidating how UPEC is able to evade host innate defenses to cause a UTI and suggest that ATG16L1 polymorphisms may be maintained in the population because of protective effects from this common infection.