title: Attenuated Bordetella pertussis vaccine candidate BPZE1 promotes human dendritic cell CCL21-induced migration and drives a Th1/Th17 response.
abstract: New vaccines against pertussis are needed to evoke full protection and long-lasting immunological memory starting from the first administration in neonates--the major target of the life-threatening pertussis infection. A novel live attenuated Bordetella pertussis vaccine strain, BPZE1, has been developed by eliminating or detoxifying three important B. pertussis virulence factors: pertussis toxin, dermonecrotic toxin, and tracheal cytotoxin. We used a human preclinical ex vivo model based on monocyte-derived dendritic cells (MDDCs) to evaluate BPZE1 immunogenicity. We studied the effects of BPZE1 on MDDC functions, focusing on the impact of Bordetella-primed dendritic cells in the regulation of Th and suppressor T cells (Ts). BPZE1 is able to activate human MDDCs and to promote the production of a broad spectrum of proinflammatory and regulatory cytokines. Moreover, conversely to its parental wild-type counterpart BPSM, BPZE1-primed MDDCs very efficiently migrate in vitro in response to the lymphatic chemokine CCL21, due to the inactivation of pertussis toxin enzymatic activity. BPZE1-primed MDDCs drove a mixed Th1/Th17 polarization and also induced functional Ts. Experiments performed in a Transwell system showed that cell contact rather than the production of soluble factors was required for suppression activity. Overall, our findings support the potential of BPZE1 as a novel live attenuated pertussis vaccine, as BPZE1-challenged dendritic cells might migrate from the site of infection to the lymph nodes, prime Th cells, mount an adaptive immune response, and orchestrate Th1/Th17 and Ts responses.
authors: Dipartimento di Malattie Infettive, Parassitarie ed Immunomediate, Istituto Superiore di Sanità, 00161 Rome, Italy. giorgio.fedele@iss.it
authors: Giorgio
authors: G
authors: Fedele
authors: Manuela
authors: M
authors: Bianco
authors: Anne-Sophie
authors: AS
authors: Debrie
authors: Camille
authors: C
authors: Locht
authors: Clara Maria
authors: CM
authors: Ausiello
mesh_terms: D001886:Bordetella pertussis; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D010567:Pertussis Vaccine / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: C515478:CCL21 protein, human; D054421:Chemokine CCL21; D016207:Cytokines; D010567:Pertussis Vaccine; D014613:Vaccines, Attenuated