Ferritinophagy drives uropathogenicEscherichia colipersistence 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.

ATG16L1 governs placental infection risk and preterm birth in mice and women

“…BeWo cells were prepared for TEM analysis as described previously (39). TEM sections were imaged using a JEOL 1200 EX transmission electron microscope (JEOL USA Inc.).…”

Iron overload and altered iron metabolism in ovarian cancer

“…Siderophores enable bacteria to solubilize iron from their environment to promote their cellular proliferation (Ellermann and Arthur, 2016). For example, uropathogenic E. coli (UPEC) bacteria depend on iron for growth and the ferritinophagy pathway was recently demonstrated to contribute to its increased survival (Bauckman and Mysorekar, 2016). It is suggested that epigenetic changes (i.e., methylation of CDKN2A) in the host uroepithelial cells due to UPEC infection may lead to bladder cancer (Tolg et al, 2011).…”

Macrophagic control of the response to uropathogenic E. coli infection by regulation of iron retention in an IL‐6‐dependent manner

“…In addition, UPEC had no significant effect on pMac survival at these time‐points (data not shown). We have previously shown that iron alone promotes UPEC growth in minimal media and in bladder epithelial cells ; thus, the UPEC growth restriction observed in macrophages is attributable to macrophage function.…”

“…This is especially relevant in vivo, since macrophages may be exposed to different concentrations of iron over the course of an infection [4]. Interestingly, the host epithelial-iron interactions have the opposite effect on bacterial survival, as our previous work has shown that UPEC is able to access iron within bladder epithelial cells via ferritinophagy, thereby promoting UPEC survival and growth within these cells [19]. We suggest that in the bladder mucosa, UPEC survival and growth within the bladder epithelium may be mitigated by the bladder macrophagic anti-microbial iron regulation response, consistent with previous data showing increased bladder macrophage counts up to 48 hpi with UPEC [40].…”