Deletion of BCG_2432c from the Bacillus Calmette‐Guérin vaccine enhances autophagy‐mediated immunity against tuberculosis. Issue 2 (7th November 2021)

• Record Type: Journal Article
• Authors: Wu, Yaqi; Tian, Maopeng; Zhang, Yandi; Peng, Huiming; Lei, Qing; Yuan, Xuefeng; Liu, Shijie; Xiong, Yulong; Lin, Xiaosong; Jo‐Lewis, Banga Ndzouboukou; Yao, Zongjie; Fu, Hui; Fan, Xionglin
• Is Part Of: Allergy. Volume 77:Issue 2(2022)
• Page Start: 619
• Page End: 632
• Publication Date: 2021-11-07
• Subjects: autophagy -- BCG_2432c -- recombinant BCG -- tuberculosis -- vaccine; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.15158
• Languages: English
• ISSNs: 0105-4538

Abstract

Abstract: Background: Mycobacterium bovis bacillus Calmette‐Guérin (BCG) is an attenuated live vaccine that provides insufficient protection against tuberculosis (TB), the underlying mechanisms for which remain unknown. Assuming that the BCG vaccine inherits immune evasive strategies from virulent parent M. bovis strains, we aimed to identify the associated genes and assess their effects on the vaccine efficacy. Methods: Three genes, BCG_3174, BCG_1782, and BCG_2432c, associated with immune evasion were first identified via bioinformatics analysis and then confirmed in the genome of M. bovis and 12 commercial BCG vaccine substrains using Polymerase Chain Reaction (PCR) and DNA sequencing. These genes were disrupted to develop mutant strains, and their effects on autophagy and their protective efficacy were further compared with the BCG vaccine in vitro and in vivo. Results: Of the three identified genes, only the disruption of BCG_2432c, namely ΔBCG_2432c, conferred stronger protection against intranasal TB in vaccinated mice, when compared with the BCG vaccine. ΔBCG_2432c showed a stronger ability to trigger intracellular ROS‐mediated complete autophagic flux in infected THP‐1 cells that resulted in higher antigen presentation. The improved protection could be attributed to early and increased IFN‐γ + CD4 + TEM and IL‐2 + CD4 + TCM cells in the spleens and lungs of ΔBCG_2432c‐vaccinated mice. Conclusions: The insufficient efficacy of the BCG vaccine is attributable to the important autophagy‐inhibition gene BCG_2432c that blocks the autophagosome‐lysosome pathway of antigen presentation. ΔBCG_2432c provides a promising platform to either replace the current BCG vaccine or develop vaccines that are more effective against TB. Abstract : ΔBCG_2432c showed a stronger ability to trigger intracellular ROS‐mediated complete autophagic flux in infected THP‐1 cells that resulted in higher antigen presentation. ΔBCG_2432c induced higher numbers of IFN‐γ + CD4 + TEM and IL‐2 + CD4 + TCM cells than BCGWT . ΔBCG_2432c confers stronger protection against TB. Abbreviations: Ag, antigen; BCG, Bacillus Calmette‐Guérin; CFU, colony‐forming units; ROS, reactive oxygen species; TEM, effector memory T cell; TCM, central memory T cell; TB, tuberculosis; THP‐1, human monocytic leukemia cell line; WT, wild type.