title: Protective role of adenylate cyclase in the context of a live pertussis vaccine candidate.
abstract: Despite high vaccination coverage, pertussis remains an important respiratory infectious disease and the least-controlled vaccine-preventable infectious disease in children. Natural infection with Bordetella pertussis is known to induce strong and long-lasting immunity that wanes later than vaccine-mediated immunity. Therefore, a live attenuated B. pertussis vaccine, named BPZE1, has been developed and has recently completed a phase I clinical trial in adult human volunteers. In this study, we investigated the contribution of adenylate cyclase (CyaA) in BPZE1-mediated protection against pertussis. A CyaA-deficient BPZE1 mutant was thus constructed. Absence of CyaA did not compromise the adherence properties of the bacteria onto mammalian cells. However, the CyaA-deficient mutant displayed a slight impairment in the ability to survive within macrophages compared to the parental BPZE1 strain. In vivo, whereas the protective efficacy of the CyaA-deficient mutant was comparable to the parental strain at a vaccine dose of 5 × 10(5) colony forming units (CFU), it was significantly impaired at a vaccine dose of 5 × 10(3) CFU. This impairment correlated with impaired lung colonization ability, and impaired IFN-γ production in the animal immunized with the CyaA-deficient BPZE1 mutant while the pertussis-specific antibody profile and Th17 response were comparable to those observed in BPZE1-immunized mice. Our findings thus support a role of CyaA in BPZE1-mediated protection through induction of cellular mediated immunity.
authors.affiliation: Department of Microbiology, National University of Singapore, CeLS Building #03-05, 28 Medical Drive, 115597 Singapore, Singapore; Immunology Programme, National University of Singapore, CeLS Building #03-05, 28 Medical Drive, 115597 Singapore, Singapore.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lim
authors.affiliation: Department of Microbiology, National University of Singapore, CeLS Building #03-05, 28 Medical Drive, 115597 Singapore, Singapore; Immunology Programme, National University of Singapore, CeLS Building #03-05, 28 Medical Drive, 115597 Singapore, Singapore.
authors.forename: Jowin K W
authors.initials: JK
authors.lastname: Ng
authors.affiliation: Inserm, U1019, F-59019 Lille, France; CNRS UMR8204, F-59019 Lille, France; Univ Lille Nord de France, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Locht
authors.affiliation: Department of Microbiology, National University of Singapore, CeLS Building #03-05, 28 Medical Drive, 115597 Singapore, Singapore; Immunology Programme, National University of Singapore, CeLS Building #03-05, 28 Medical Drive, 115597 Singapore, Singapore. Electronic address: micas@nus.edu.sg.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Alonso
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D001886:Bordetella pertussis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D017353:Gene Deletion; D023061:Gene Order; D006801:Humans; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D010567:Pertussis Vaccine / Q000235:genetics* / Q000276:immunology*; D010641:Phenotype; D014613:Vaccines, Attenuated / Q000235:genetics* / Q000276:immunology*; D014917:Whooping Cough / Q000276:immunology / Q000517:prevention & control*
chemical_list: D000907:Antibodies, Bacterial; D016207:Cytokines; D010567:Pertussis Vaccine; D014613:Vaccines, Attenuated; D000262:Adenylyl Cyclases
keywords: Adenylate cyclase; BPZE1; Bordetella pertussis