title: Differentially imprinted innate immunity by mucosal boost vaccination determines antituberculosis immune protective outcomes, independent of T-cell immunity.
abstract: Homologous and heterologous parenteral prime-mucosal boost immunizations have shown great promise in combating mucosal infections such as tuberculosis and AIDS. However, their immune mechanisms remain poorly defined. In particular, it is still unclear whether T-cell and innate immunity may be independently affected by these immunization modalities and how it impacts immune protective outcome. Using two virus-based tuberculosis vaccines (adenovirus (Ad) and vesicular stomatitis virus (VSV) vectors), we found that while both homologous (Ad/Ad) and heterologous (Ad/VSV) respiratory mucosal boost immunizations elicited similar T-cell responses in the lung, they led to drastically different immune protective outcomes. Compared with Ad-based boosting, VSV-based boosting resulted in poorly enhanced protection against tuberculosis. Such inferior protection was associated with differentially imprinted innate phagocytes, particularly the CD11c(+)CD11b(+/-) cells, in the lung. We identified heightened type 1 interferon (IFN) responses to be the triggering mechanism. Thus, increased IFN-β severely blunted interleukin-12 responses in infected phagocytes, which in turn impaired their nitric oxide production and antimycobacterial activities. Our study reveals that vaccine vectors may differentially imprint innate cells at the mucosal site of immunization, which can impact immune-protective outcome, independent of T-cell immunity, and it is of importance to determine both T-cell and innate cell immunity in vaccine studies.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Jeyanathan
authors.forename: D
authors.initials: D
authors.lastname: Damjanovic
authors.forename: C R
authors.initials: CR
authors.lastname: Shaler
authors.forename: R
authors.initials: R
authors.lastname: Lai
authors.forename: M
authors.initials: M
authors.lastname: Wortzman
authors.forename: C
authors.initials: C
authors.lastname: Yin
authors.forename: A
authors.initials: A
authors.lastname: Zganiacz
authors.forename: B D
authors.initials: BD
authors.lastname: Lichty
authors.forename: Z
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005822:Genetic Vectors / Q000276:immunology*; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology*; D018353:Rhabdoviridae Infections / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage*; D018116:Vesiculovirus / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D032581:Tuberculosis Vaccines; D018664:Interleukin-12; D009569:Nitric Oxide