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A Bacterial Flagellin, Vibrio vulnificus FlaB, Has a Strong Mucosal Adjuvant Activity To Induce Protective Immunity

Research Institute of Vibrio Infection and Genome Research Center for Enteropathogenic Bacteria,¹ National Research Laboratory of Molecular Microbial Pathogenesis and Department of Microbiology, Chonnam National University Medical School, Gwangju 501-746, South Korea,³ Department of Dental Pharmacology, Chonnam Dental Research Institute, College of Dentistry, Chonnam National University, Gwangju 500-757, South Korea,² Departments of Internal Medicine,⁴ Nuclear Medicine, Chonnam National University Hwasun Hospital, 160 Ilsim-ri, Hwasoon, Chonnam 519-809, South Korea,⁵ Department of Microbiology, Hanyang University College of Medicine, Seoul 133-791, South Korea,⁶ Mucosal Immunology Section, International Vaccine Institute, Seoul 151-818, South Korea⁷

Received 2 November 2004/ Returned for modification 30 December 2004/ Accepted 5 October 2005

Flagellin, the structural component of flagellar filament in various locomotive bacteria, is the ligand for Toll-like receptor 5 (TLR5) of host cells. TLR stimulation by various pathogen-associated molecular patterns leads to activation of innate and subsequent adaptive immune responses. Therefore, TLR ligands are considered attractive adjuvant candidates in vaccine development. In this study, we show the highly potent mucosal adjuvant activity of a Vibrio vulnificus major flagellin (FlaB). Using an intranasal immunization mouse model, we observed that coadministration of the flagellin with tetanus toxoid (TT) induced significantly enhanced TT-specific immunoglobulin A (IgA) responses in both mucosal and systemic compartments and IgG responses in the systemic compartment. The mice immunized with TT plus FlaB were completely protected from systemic challenge with a 200x minimum lethal dose of tetanus toxin. Radiolabeled FlaB administered into the nasal cavity readily reached the cervical lymph nodes and systemic circulation. FlaB bound directly to human TLR5 expressed on cultured epithelial cells and consequently induced NF-B and interleukin-8 activation. Intranasally administered FlaB colocalized with CD11c as patches in putative dendritic cells and caused an increase in the number of TLR5-expressing cells in cervical lymph nodes. These results indicate that flagellin would serve as an efficacious mucosal adjuvant inducing protective immune responses through TLR5 activation.

Editor: V. J. DiRita

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