title: ATG16L1 and pathogenesis of urinary tract infections.
abstract: Autophagy is generally considered to be antipathogenic. The autophagy gene ATG16L1 has a commonly occurring mutation associated with Crohn disease (CD) and intestinal cell abnormalities. Mice hypomorphic for ATG16L1 (ATG16L1(HM)) recreate specific features of CD. Our recent study shows that the same ATG16L1(HM) mice that are susceptible to intestinal inflammatory disease are protected from urinary tract infections (UTI), a common and important human disease primarily caused by uropathogenic E. coli (UPEC). UPEC colonize the bladder and exhibit both luminal and intra-epithelial stages. The host responds by recruiting innate immune cells and shedding infected epithelial cells to clear infection. Despite these countermeasures, UPEC can persist within the bladder epithelium as membrane-enclosed quiescent intracellular reservoirs (QIRs) that can seed recurrent UTI. The mechanisms of persistence remain unknown. In this study, we show that ATG16L1 deficiency protects the host against acute UTI and UPEC latency. ATG16L1(HM) mice clear urinary bacterial loads more rapidly and thoroughly due to ATG16L1-deficient innate immune components. Furthermore, ATG16L1(HM) mice exhibit superficial urothelial cell-autonomous architectural aberrations that also result in significantly reduced QIR numbers. Our findings reveal a host-protective effect of ATG16L1 deficiency in vivo against a common pathogen.
authors.affiliation: Department of Obstetrics and Gynecology, Washington University School of Medicine St. Louis, St. Louis, MO, USA.
authors.forename: Caihong
authors.initials: C
authors.lastname: Wang
authors.forename: Jane W
authors.initials: JW
authors.lastname: Symington
authors.forename: Indira U
authors.initials: IU
authors.lastname: Mysorekar
mesh_terms: D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D007109:Immunity; D051379:Mice; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D014552:Urinary Tract Infections / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D056689:Uropathogenic Escherichia coli / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D002352:Carrier Proteins