Uropathogenic Escherichia coli (UPEC) are a common cause of urinary tract infections (UTIs) in humans. While the importance of natural killer (NK) cells in innate immune protection against tumors and viral infections is well documented, their role in defense against bacterial infections is still emerging, and their involvement in UPEC-mediated UTI is practically unknown. Using a systematic mutagenesis approach, we found that UPEC adheres to NK cells primarily via its type I fimbriae and employs its hemolysinA toxin to kill NK cells. In the absence of hemolysinA, NK cells directly respond to the bacteria and secrete the cytokine TNF-α, which results in decreased bacterial numbers in vitro and reduction of bacterial burden in the infected bladders. Thus, NK cells control UPEC via TNF-α production, which UPEC counteracts by hemolysinA-mediated killing of NK cells, representing a previously unrecognized host defense and microbial counterattack mechanism in the context of UTI.
Bibliographical noteFunding Information:
This study was supported by the Advanced ERC grant, by The Israeli Science Foundation, by The Israeli- I-CORE, by the GIF Foundation, and by The ICRF Professorship Grant (all to O.M.) and by the Israeli Science Foundation (to G.B.). The work was also supported by the Israeli Science Foundation (to C.G.). O.M. is a Crown Professor of Molecular Immunology. C.G. is supported by the Foulkes Foundation. The authors would like to thank Professors Hirotada Mori and Toru Nakayashiki for useful discussion. The authors would also like to thank Professor Saul Burdman, who kindly supplied the pMODkan plasmid. The pGNH404 plasmid was a gift from Professor Agneta Richter-Dahlfors. Bacterial strains CFT073, UPEC76, CFT073ON, CFT073OFF, and CFT fim/pap were from Professor Harry Mobley’s collection. The authors thank Professor Ilan Rosenshine for the EPEC E2348/69 strain and Professor Nahum Shpigel for the UTI89 and UTI536 strains. The authors are grateful to the EM Unit of Core Research Facility of the Faculty of Medicine, The Hebrew University Jerusalem, for assistance with electron microscopy.