Survival advantage of E. coli in the inflamed gut is mechanistically linked to enterobactin-mediated inhibition of myeloperoxidase and regulation by lipocalin 2
Beng San Yeoh
Graduate Student
Huck Institutes of the Life Sciences
Penn State University, University Park, PA 16802
Beng San Yeoh, Vishal Singh, Xia Xiao, Manish Kumar, Michael Bachman, Niels Borregaard, Bina Joe, and Matam Vijay-Kumar
During an inflammatory response in the gut, several commensal bacteria such as E. coli not only survive but also thrive and consequently contribute to the disease pathogenesis. The mechanisms by which such opportunistic pathogens bloom despite the hostile pro-inflammatory milieu of the inflamed gut remain largely unknown. We demonstrate that enterobactin (Ent), a siderophore released by E. coli, is a potent inhibitor of a key bactericidal enzyme of the host innate immune system, myeloperoxidase (MPO). The inhibitory activity is specific, such that glycosylated Ent (salmochelin) and non-catecholate siderophores (i.e. yersiniabactin and ferrichrome) failed to inhibit MPO activity. An E. coli ferrienterobactin permease mutant (ΔfepA) which overexpresses Ent, but not the 3-dehydroquinate synthase and ferrienterobactin permease double mutant (ΔaroB/ΔfepA), inhibited MPO activity and exhibited enhanced survival in inflamed guts. This survival advantage was counter-regulated by the host siderophore binding protein, lipocalin 2, which rescued MPO from Ent-mediated inhibition. Spectral analysis revealed that Ent interferes with compound I [oxoiron, Fe(IV)=O] and reverts the enzyme back to its native ferric [Fe(III)] state. These findings define a fundamental mechanism by which E. coli surpasses the host innate immune responses during inflammatory gut diseases and gains a distinct survival advantage.
