Abstract
The immunogenicity of bacterial flagellin has been reported in different studies. By its close interaction with the immune system, the flagellin represents an interesting adjuvant and vaccine candidate. Salmonella Typhimurium flagellin has already been tested as adjuvant to stimulate mucosal immunity. Here, we assessed the ability of Clostridium difficile flagellin FliC to act as a mucosal adjuvant, first combined with ovalbumin as antigen and second with a C. difficile surface protein, the precursor of the S-layer proteins SlpA. Using ovalbumin as antigen, we compared the gut mucosal adjuvanticity of FliC to Salmonella Typhimurium flagellin and cholera toxin. Two routes of immunization were tested in a mouse model: intra-rectal and intra-peritoneal, following which, gut mucosal and systemic antibody responses against ovalbumin (Immunoglobulins G and Immunoglobulins A) were analyzed by Enzyme-Linked Immuno Assay in intestinal contents and in sera. In addition, ovalbumin-specific immunoglobulin producing cells were detected in the intestinal lamina propria by Enzyme-Linked Immunospot. Results showed that FliC as adjuvant for immunization targeting ovalbumin was able to stimulate a gut mucosal and systemic antibody response independently of the immunization route. In order to develop a mucosal vaccine to prevent C. difficile intestinal colonization, we assessed in a mouse model the efficacy of FliC as adjuvant compared with cholera toxin co-administrated with the C. difficile S-layer precursor SlpA as antigen. After challenge, a significant decrease of C. difficile intestinal colonization was observed in immunized groups compared to the control group. Our results showed that C. difficile FliC could be used as adjuvant in mucosal vaccination strategy against C. difficile infections.
Highlights
Clostridium difficile is an anaerobic spore-forming Gram positive bacterium, commonly found in the environment and frequently isolated in hospitals
Despite inter-individual variation, a significant greater production of OVA specific IgA was observed with FliC as adjuvant compared to mice immunized with cholera toxin (CT) (p = 0.019) and phosphate-buffered saline (PBS) control mice (p = 0.020)
We assessed the adjuvant property of C. difficile flagellin FliC in comparison to flagellin FLA-ST and CT, using OVA as antigen in mice
Summary
Clostridium difficile is an anaerobic spore-forming Gram positive bacterium, commonly found in the environment and frequently isolated in hospitals. Clostridium difficile FliC interest in mucosal vaccine responsible for diarrhea and pseudomembranous colitis associated to gut microbiota dysbiosis frequently consecutive to antibiotic therapy in the elderly [1]. The toxins TcdA and TcdB are the main virulence factors responsible for the clinical signs Several vaccines targeting these toxins are under investigation in clinical trials and seem to show efficacy after parenteral immunization (clinical trials Sanofi Pasteur NCT01887912, Pfizer NCT03090191). Intestinal colonization is the first step of the C. difficile pathogenic process; targeting colonization factors represents an interesting vaccine strategy. Besides the identification of the antigenic target, a better knowledge of the protective immune response against C. difficile and the respective role of the local and systemic response will improve vaccine development [12]. For vaccine design, the choice of the adjuvant related to the administration route is crucial to optimize immune response [13]
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