Correlates of Protection in Response to Mucosal Vaccination with Uropathogenic Escherichia coli Antigens and the Role of IL-17A during Urinary Tract Infection.

Abstract

Urinary tract infection (UTI) caused by uropathogenic Escherichia coli (UPEC) is a substantial economic and societal burden – a formidable public health issue. Despite significant advances in our understanding of the biology of UPEC, the mechanism by which the host successfully responds to UTI and a full comprehension of genetic loci that influence susceptibility are not yet in place. While there is an appreciation for the role of classic innate immune responses that occur during UPEC-mediated UTI, there is a clear disconnect regarding how these factors stimulate acquired immunity that facilitates bacterial clearance upon reinfection. Unraveling the molecular details of this process is vital to understanding the host response to UTI and developing a successful vaccine to prevent human UTI. Herein, the immune response to and efficacy of outer membrane iron receptor proteins delivered intranasally is demonstrated. Correlates of protection – the immunoglobulin “class switch index” and relative abundance of bladder urinary IgA – were identified by testing the immune responses to vaccination with both successful and unsuccessful vaccine candidates. In this study, splenocytes from mice vaccinated intranasally secreted high concentrations of the proinflammatory cytokine IL-17A in response to in vitro restimulation. From this observation, a study was conducted using IL-17A-/- mice as a murine model of ascending UTI to determine the role of IL-17A in both the innate and the adaptive immune response to experimental UPEC-mediated UTI. While IL-17A appeared to be dispensable for the development of adaptive immune responses that result in enhanced clearance, IL-17A was clearly important to control the bacterial burdens of primary infection. Both gammadelta-positive cells and an inflammatory monocyte population appear to represent sources of IL-17A. Not surprisingly, IL-17A was found to play a role in regulating inflammatory responses in the murine bladder, crucial events for efficient clearance of UPEC during acute infection. These results advance our understanding of the innate immune response to UPEC-mediated UTI, and provide a means to more efficiently evaluate future vaccine candidates in an effort to develop an efficacious vaccine to prevent UTI.