Harnessing the Immunomodulatory Properties of Bacterial Ghosts to Boost the Anti-mycobacterial Protective Immunity

Frontiers in Immunology

Werner Lubitz¹  Giorgia Pastorin²  Pavol Kudela²  Sylvie Alonso⁴  Paola Florez De Sessions⁵  Dawn Poh Sum Choi⁵  Balamurugan Periaswamy⁵  Vanessa Hui Qi Koh⁶  Sharol Su Lei Cho⁶  Jieling Lim⁶  Maurizio Vacca⁶ 

[1] Consulting (BIRD-C), Vienna, Austria;;Biotech Innovation Research Development &Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore;Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore;Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore;Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore;

关键词: bacterial ghosts;    tuberculosis;    host-directed therapy;    drug resistance;    adjunct immune therapy;   

DOI  :  10.3389/fimmu.2019.02737

来源: DOAJ

【 摘 要 】

Tuberculosis (TB) pathogenesis is characterized by inadequate immune cell activation and delayed T cell response in the host. Recent immunotherapeutic efforts have been directed at stimulating innate immunity and enhancing interactions between antigen presenting cells and T cells subsets to improve the protective immunity against TB. In this study, we investigated the immunostimulatory properties of bacterial ghosts (BG) as a novel approach to potentiate the host immunity against mycobacterial infection. BG are intact cytoplasm-free Escherichia coli envelopes and have been developed as bacterial vaccines and adjuvant/delivery system in cancer immunotherapy. However, BG have yet to be exploited as immunopotentiators in the context of infectious diseases. Here, we showed that BG are potent inducers of dendritic cells (DC), which led to enhanced T cell proliferation and differentiation into effector cells. BG also induced macrophage activation, which was associated with enhanced nitric oxide production, a key anti-mycobacterial weapon. We further demonstrated that the immunostimulatory capability of BG far exceeds that of LPS and involves both TLR4-dependent and independent pathways. Consistently, BG treatment, but not LPS treatment, reduced the bacterial burden in infected mice, which correlated with increased influx of innate and adaptive effector immune cells and increased production of key cytokines in the lungs. Finally and importantly, enhanced bacilli killing was seen in mice co-administered with BG and second-line TB drugs bedaquiline and delamanid. Overall, this work paves the way for BG as potent immunostimulators that may be harnessed to improve mycobacteria killing at the site of infection.

【 授权许可】

Unknown