Mucosal Immunization with Iron Receptor Antigens Protects against Urinary Tract Infection

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Abstract
Uncomplicated infections of the urinary tract, caused by uropathogenic Escherichia coli, are among the most common diseases requiring medical intervention. A preventive vaccine to reduce the morbidity and fiscal burden these infections have upon the healthcare system would be beneficial. Here, we describe the results of a large-scale selection process that incorporates bioinformatic, genomic, transcriptomic, and proteomic screens to identify six vaccine candidates from the 5379 predicted proteins encoded by uropathogenic E. coli strain CFT073. The vaccine candidates, ChuA, Hma, Iha, IreA, IroN, and IutA, all belong to a functional class of molecules that is involved in iron acquisition, a process critical for pathogenesis in all microbes. Intranasal immunization of CBA/J mice with these outer membrane iron receptors elicited a systemic and mucosal immune response that included the production of antigen-specific IgM, IgG, and IgA antibodies. The cellular response to vaccination was characterized by the induction and secretion of IFN-γ and IL-17. Of the six potential vaccine candidates, IreA, Hma, and IutA provided significant protection from experimental infection. In immunized animals, class-switching from IgM to IgG and production of antigen-specific IgA in the urine represent immunological correlates of protection from E. coli bladder colonization. These findings are an important first step toward the development of a subunit vaccine to prevent urinary tract infections and demonstrate how targeting an entire class of molecules that are collectively required for pathogenesis may represent a fundamental strategy to combat infections. Because urinary tract infections (UTIs) are a significant healthcare burden, it would be beneficial to develop a vaccine to prevent uncomplicated UTI caused by Escherichia coli. Using a large-scale screening process we uniformly identified proteins involved in iron uptake as potential vaccine candidates against E. coli. Iron acquisition is a critical function required by bacteria in order to cause infections. In uropathogenic Escherichia coli, this function is mediated by a repertoire of systems that scavenge iron from the host during infection. We found that vaccination with certain iron receptors from these systems is sufficient to elicit protective immunity from experimental urinary tract infection. Induction of an antibody response played a key role in protection from infection because antibody class-switching and the production of antibodies in urine correlated with reduced numbers of bacteria in the bladder. By targeting an entire class of molecules involved in iron acquisition instead of a single protein, it was possible to successfully identify components of a protective UTI vaccine. This strategy could be a useful approach in the development of vaccines to prevent infections caused by other pathogenic bacteria.

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