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Nanoparticle-Fusion protein complexes protect against Mycobacterium tuberculosis infection

Hart, P; Copland, A; Reynolds Diogo, G; Harris, S; Spallek, R; Oehlmann, W; Singh, M; Basile, J; Rottenberg, M; Paul, M; et al. Hart, P; Copland, A; Reynolds Diogo, G; Harris, S; Spallek, R; Oehlmann, W; Singh, M; Basile, J; Rottenberg, M; Paul, M; Reljic, R (2018) Nanoparticle-Fusion protein complexes protect against Mycobacterium tuberculosis infection. Molecular Therapy, 26 (3). pp. 822-833. ISSN 1525-0024 https://doi.org/10.1016/j.ymthe.2017.12.016
SGUL Authors: Reljic, Rajko

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Abstract

Tuberculosis (TB) is the leading cause of death from infectious disease, and the current vaccine, Bacillus Calmette-Guerin (BCG), is inadequate. Nanoparticles (NPs) are an emerging vaccine technology, with recent successes in oncology and infectious diseases. NPs have been exploited as antigen delivery systems and also for their adjuvantic properties. However, the mechanisms underlying their immunological activity remain obscure. Here, we developed a novel mucosal TB vaccine (Nano-FP1) based upon yellow carnauba wax NPs (YC-NPs), coated with a fusion protein consisting of three Mycobacterium tuberculosis (Mtb) antigens: Acr, Ag85B, and HBHA. Mucosal immunization of BCG-primed mice with Nano-FP1 significantly enhanced protection in animals challenged with low-dose, aerosolized Mtb. Bacterial control by Nano-FP1 was associated with dramatically enhanced cellular immunity compared to BCG, including superior CD4+ and CD8+ T cell proliferation, tissue-resident memory T cell (Trm) seeding in the lungs, and cytokine polyfunctionality. Alongside these effects, we also observed potent humoral responses, such as the generation of Ag85B-specific serum IgG and respiratory IgA. Finally, we found that YC-NPs were able to activate antigen-presenting cells via an unconventional IRF-3-associated activation signature, without the production of potentially harmful inflammatory mediators, providing a mechanistic framework for vaccine efficacy and future development.

Item Type: Article
Additional Information: © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Biotechnology, 06 Biological Sciences, 10 Technology, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Molecular Therapy
ISSN: 1525-0024
Dates:
DateEvent
7 March 2018Published
22 December 2017Published Online
18 December 2017Accepted
Projects:
Project IDFunderFunder ID
643558Horizon 2020UNSPECIFIED
URI: https://openaccess.sgul.ac.uk/id/eprint/109760
Publisher's version: https://doi.org/10.1016/j.ymthe.2017.12.016

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