Autophagy-driven MHC-I downregulation enables NK cell-mediated clearance of intracellular uropathogenic <i>E. coli</i> in urinary tract infection

Uropathogenic <i>E. coli</i> (UPEC) accounts for over 80% of urinary tract infections (UTIs) due to its distinct capacity to invade and persist within bladder epithelial cells (BECs). The ability of UPEC to survive for extended periods within BECs can also contribute to the recurrence of UTIs. Since natural killer (NK) cells are part of the innate immune defense with a unique capacity to kill intracellular bacteria, we aimed to examine the potential role of these cells in bacterial clearance during UTIs. Here, we report that infecting mouse bladders with UPEC promoted a significant recruitment of NK cells to UPEC-infected BECs. Depletion of NK cells using neutralizing antibodies increased the bacterial load in the infected bladder, indicating a protective role for NK cells against the host. Co-culturing BECs harboring intracellular UPECs with NK cells in vitro significantly reduced the intracellular bacterial burden in BECs. The targeting of infected BECs by NK cells required reduced major histocompatibility complex (MHC) class I (MHC-I) expression, an inhibitory signal on NK cells, a process facilitated by autophagy, and concurrent increased CD48 expression on BECs, a ligand that activates NK cells. The recruitment of NK cells to UPEC-infected BECs was mediated by chemokines CXCL10 and CXCL12. Administering the IL-15/IL-15Rα supercomplex, a potent activator of NK cells, to UPEC-infected mice significantly reduced the bacterial load in the bladder. These observations highlight NK cells as an overlooked component in the innate immune defense against UTIs and a potential therapeutic target.