Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.

Publication date: Nov 30, 2023

Bacillus Calmette-GucE9rin (BCG) vaccination induces a type of immune memory known as “trained immunity”, characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCG significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCG enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCG vaccination. Most noteworthy, utilizing rBCG’s higher-up trained effects: The single mucosal immunization with rBCG-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces.

Concepts Keywords
Boosted Bacille Calmette-Guerin
Coronavirus glycolysis
Immunometabolic innate immune memory
Mice mucosal vaccination
Recombinant Trained immunity

Semantics

Type Source Name
disease VO recombinant BCG vaccine
drug DRUGBANK BCG vaccine
disease VO vaccination
disease IDO immune response
disease MESH reinfection
disease VO immunization
pathway REACTOME Metabolism
pathway KEGG Coronavirus disease
disease VO vaccine
disease MESH tuberculosis
pathway KEGG Tuberculosis

Original Article

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