Date of Award

January 2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

David S. Bradley

Abstract

Despite widespread vaccination, Bordetella pertussis, the causative agent of whooping cough, is still a threat to global health. One cause of pertussis reemergence observed in many countries is ineffective immunity generated by the current acellular pertussis (aP) vaccines. Interestingly, recent studies have shown that TLR stimulating agents can enhance aP vaccine induced immunity. Type III secretion (T3S) system needle proteins from many gram-negative bacteria have been shown to be strong TLR agonists that induce NF-B/AP-1 signaling and promote inflammatory cytokine release from innate cells in vitro. In this study, we investigated the immune modulating properties of BscF, a purified T3S system needle protein from B. pertussis. In addition, we characterized the ability of BscF to enhance aP vaccine induced immunity. In the current study, we demonstrated that BscF is a strong TLR2 and TLR4 agonist that induced NF-B/AP-1 activation and promoted inflammatory cytokine release, augmented by clathrin-mediated endocytosis. In vivo, BscF immunization induced robust antibody responses, strong Th1 and Th17 responses from stimulated splenocytes, and provided modest protection against B. pertussis challenge. BscF also enhanced aP induced immunity and reduced lung bacterial burden in mice challenged with B. pertussis. These results demonstrate that BscF has considerable potential to be included in a next-generation B. pertussis aP vaccine.

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