The Yersiniabactin System is a Uropathogenic Escherichia coli Virulence Factor and Novel Vaccine Target to Prevent Urinary Tract Infection.

Abstract

Urinary tract infections (UTIs) are common, with nearly half of all women and 12% of men experiencing at least one UTI in their lifetime. While most UTIs seldom cause life-threatening or long-term health problems, the regularity with which they occur generates a substantial economic and public health burden. Over 80% of these infections are caused by a heterogeneous group of uropathogenic Escherichia coli (UPEC) strains, and patients are generally treated with a course of antibiotics to prevent more serious infection. However, the emergence and spread of antibiotic resistance mechanisms, such as extended-spectrum beta-lactamases and carbapenemases, complicate the successful long-term treatment of UTI and increase the potential for serious infection. As a result, novel therapeutics and preventive approaches to UTI, such as vaccination, are sought. We hypothesized that targeting nutrient acquisition in pathogenic bacteria, specifically systems that acquire iron, could provide a novel vaccine target to prevent UTI. Using a murine model of infection and recombinant UPEC antigens, we identified the yersiniabactin receptor, FyuA, as a protective vaccine candidate. Intranasal immunization with FyuA induced a robust and long-lived humoral immune response that correlated with protection against UPEC colonization in the kidneys and development of acute pyelonephritis. In addition, using a UPEC mutant unable to acquire yersiniabactin during infection, we established the yersiniabactin receptor as a UPEC virulence factor during cystitis and pyelonephritis, a fitness factor during bacteremia, and the surface- accessible target of the experimental FyuA vaccine. We were also able to validate the expression of iron acquisition systems, including the yersiniabactin system, during natural human infection by quantifying RNA transcripts, directly stabilized from E. coli in the urine of women with uncomplicated cystitis, by RNAseq analysis. These findings provide a foundation for the development of a vaccine to prevent UPEC UTI by targeting the yersiniabactin receptor, and reinforce support for the yersiniabactin system as a narrow-spectrum therapeutic target to combat multidrug-resistant pandemic clones of the family Enterobacteriaceae.