title: Airway delivery of soluble mycobacterial antigens restores protective mucosal immunity by single intramuscular plasmid DNA tuberculosis vaccination: role of proinflammatory signals in the lung.
abstract: Protection by parenteral immunization with plasmid DNA vaccines against pulmonary tuberculosis (TB) is very modest. In this study, we have investigated the underlying mechanisms for the poor mucosal protective efficacy and the avenues and mechanisms to improve the efficacy of a single i.m. immunization with a monogenic plasmid DNA TB vaccine in a murine model. We show that i.m. DNA immunization fails to elicit accumulation of Ag-specific T cells in the airway lumen despite robust T cell responses in the spleen. Such systemically activated T cells cannot be rapidly mobilized into the airway lumen upon Mycobacterium tuberculosis exposure. However, airway deposition of low doses of soluble mycobacterial Ags in previously immunized mice effectively mobilizes the systemically activated T cells into the airway lumen. A fraction of such airway luminal T cells can persist in the airway lumen, undergo quick, robust expansion and activation and provide marked immune protection upon airway M. tuberculosis exposure. Airway mucosal deposition of soluble mycobacterial Ags was found to create a tissue microenvironment rich in proinflammatory molecules including chemokines and hence conducive to T cell recruitment. Thus, in vivo neutralization of MIP-1alpha or IFN-inducible protein-10 markedly inhibited the accumulation of Ag-specific T cells in the airway lumen. Our data suggest that immunoprotective efficacy on the mucosal surface by i.m. plasmid DNA immunization could be substantially improved by simple mucosal soluble Ag inoculation and restoration of mucosal luminal T cells. Our study holds implication for the future design of DNA vaccination strategies against intracellular infections.
authors.affiliation: Centre for Gene Therapeutics, M. G. DeGroote Institute for Infectious Disease Research, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mangalakumari
authors.initials: M
authors.lastname: Jeyanathan
authors.forename: Jingyu
authors.initials: J
authors.lastname: Mu
authors.forename: Kapilan
authors.initials: K
authors.lastname: Kugathasan
authors.forename: Xizhong
authors.initials: X
authors.lastname: Zhang
authors.forename: Daniela
authors.initials: D
authors.lastname: Damjanovic
authors.forename: Cherrie
authors.initials: C
authors.lastname: Small
authors.forename: Maziar
authors.initials: M
authors.lastname: Divangahi
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054405:Chemokine CCL3 / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology; D005260:Female; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects* / Q000276:immunology; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010957:Plasmids / Q000494:pharmacology; D012137:Respiratory System / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D032581:Tuberculosis Vaccines / Q000276:immunology / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000517:prevention & control*; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000942:Antigens, Bacterial; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA