title: Ferritinophagy drives uropathogenic Escherichia coli persistence in bladder epithelial cells.
abstract: Autophagy is a cellular recycling pathway, which in many cases, protects host cells from infections by degrading pathogens. However, uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections (UTIs), persist within the urinary tract epithelium (urothelium) by forming reservoirs within autophagosomes. Iron is a critical nutrient for both host and pathogen, and regulation of iron availability is a key host defense against pathogens. Iron homeostasis depends on the shuttling of iron-bound ferritin to the lysosome for recycling, a process termed ferritinophagy (a form of selective autophagy). Here, we demonstrate for the first time that UPEC shuttles with ferritin-bound iron into the autophagosomal and lysosomal compartments within the urothelium. Iron overload in urothelial cells induces ferritinophagy in an NCOA4-dependent manner causing increased iron availability for UPEC, triggering bacterial overproliferation and host cell death. Addition of even moderate levels of iron is sufficient to increase and prolong bacterial burden. Furthermore, we show that lysosomal damage due to iron overload is the specific mechanism causing host cell death. Significantly, we demonstrate that host cell death and bacterial burden can be reversed by inhibition of autophagy or inhibition of iron-regulatory proteins, or chelation of iron. Together, our findings suggest that UPEC persist in host cells by taking advantage of ferritinophagy. Thus, modulation of iron levels in the bladder may provide a therapeutic avenue to controlling UPEC persistence, epithelial cell death, and recurrent UTIs.
authors.affiliation: a Departments of Obstetrics & Gynecology, Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Bauckman
authors.affiliation: a Departments of Obstetrics & Gynecology, Washington University School of Medicine , St. Louis , MO , USA.|b Pathology & Immunology, Washington University School of Medicine , St. Louis , MO , USA.
authors.forename: Indira U
authors.initials: IU
authors.lastname: Mysorekar
mesh_terms: D001343:Autophagy / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D004927:Escherichia coli Infections / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D001743:Urinary Bladder / Q000382:microbiology*; D014552:Urinary Tract Infections / Q000378:metabolism / Q000382:microbiology; D056689:Uropathogenic Escherichia coli
chemical_list: D007501:Iron
keywords: E. coli; NCOA4; UPEC; deferoxamine (DFO); ferric ammonium citrate (FAC); ferrum; urinary tract infections (UTIs)