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Siderophore Vaccine Conjugates Protect Against Uropathogenic Escherichia Coli Urinary Tract Infection.

Laura A. Mikea, Sara N. Smitha, Christopher A. Sumnera, Kathryn A. Eatona, and Harry L. T. Mobleya,1 aDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109 Edited by Ralph R. Isberg, Howard Hughes Medical Institute/Tufts University School of Medicine, Boston, MA, and approved October 19, 2016 (received for review April 20, 2016) Significance Urinary tract infections (UTIs) are primarily caused by uropathogenic Escherichia coli (UPEC), and 1 in 40 women experience chronic UTIs during their lifetime. The antibiotic courses required to treat infections promote antibiotic resistance, and current vaccine options offer limited protection. We have pioneered a strategy using small iron-chelating compounds called siderophores as vaccine antigens. These siderophores are not produced by commensal bacteria and are required for UTI. The siderophore vaccines reported here are easy to formulate and reduce bacterial burdens in a murine model of UTI. This report highlights the untapped resource of bacteria-specific small molecules as potential vaccine antigens and provides a proof of principle for incorporating these compounds into multicomponent vaccines for the prevention of bacterial infections. Abstract Uropathogenic Escherichia coli (UPEC) is the primary cause of uncomplicated urinary tract infections (UTIs). Whereas most infections are isolated cases, 1 in 40 women experience recurrent UTIs. The rise in antibiotic resistance has complicated the management of chronic UTIs and necessitates new preventative strategies. Currently, no UTI vaccines are approved for use in the United States, and the development of a highly effective vaccine remains elusive. Here, we have pursued a strategy for eliciting protective immunity by vaccinating with small molecules required for pathogenesis, rather than proteins or peptides. Small iron-chelating molecules called siderophores were selected as antigens to vaccinate against UTI for this vaccine strategy. These pathogen-associated stealth siderophores evade host immune defenses and enhance bacterial virulence. Previous animal studies revealed that vaccination with siderophore receptor proteins protects against UTI. The poor solubility of these integral outer-membrane proteins in aqueous solutions limits their practical utility. Because their cognate siderophores are water soluble, we hypothesized that these bacterial-derived small molecules are prime vaccine candidates. To test this hypothesis, we immunized mice with siderophores conjugated to an immunogenic carrier protein. The siderophore-protein conjugates elicited an adaptive immune response that targeted bacterial stealth siderophores and protected against UTI. Our study has identified additional antigens suitable for a multicomponent UTI vaccine and highlights the potential use of bacterial-derived small molecules as antigens in vaccine therapies. Both the physical and financial burdens of urinary tract infections (UTIs) are staggering. Half of all women experience a symptomatic UTI in their lifetime (1). And of those women, almost half suffer a reoccurrence within the next year (1). In the United States, where the annual societal cost of UTI is likely underestimated at $3.5 billion (2), 4 million women have UTIs continuously (3). Uropathogenic Escherichia coli (UPEC) is a subclass of extraintestinal pathogenic E. coli (ExPEC) and is the etiological agent for 80% of all uncomplicated UTIs (1). In 2006, there were 11 million physician visits, over 1.7 million emergency room visits, and 479,000 hospitalizations of both men and women in the United States for UTI (2, 4). Altogether, these estimates place UTIs first among kidney and urologic diseases in terms of total cost. UTIs occur when bacteria, most commonly UPEC (5), contaminate the periurethral area and traverse the urethra to colonize the bladder and its underlying epithelium, causing cystitis (6, 7). If left untreated, UPEC may ascend theRead more…

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