Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in mice

Abstract

Bacillus Calmette-Guérin (BCG) is a licensed prophylactic vaccine against tuberculosis (TB). Current TB vaccine efforts focus on improving BCG effects through recombination or genetic attenuation and/or boost with different vaccines. Recent years, it was revealed that BCG could elicit non-specific heterogeneous protection against other pathogens such as viruses through a process termed trained immunity. Previously, we constructed a recombinant BCG (rBCG-DisA) with elevated c-di-AMP as endogenous adjuvant by overexpressing di-adenylate cyclase of Mycobacterium tuberculosis DisA, and found that rBCG-DisA induced enhanced immune responses by subcutaneous route in mice after M. tuberculosis infection. In this study, splenocytes from rBCG-DisA immunized mice by intravenous route (i.v) elicited greater proinflammatory cytokine responses to homologous and heterologous re-stimulations than BCG. After M. tuberculosis infection, rBCG-DisA immunized mice showed hallmark responses of trained immunity including potent proinflammatory cytokine responses, enhanced epigenetic changes, altered lncRNA expressions and metabolic rewiring in bone marrow cells and other tissues. Moreover, rBCG-DisA immunization induced higher levels of antibodies and T cells responses in the lung and spleen of mice after M. tuberculosis infection. It was found that rBCG-DisA resided longer than BCG in the lung of M. tuberculosis infected mice implying prolonged duration of vaccine efficacy. Then, we found that rBCG-DisA boosting could prolong survival of BCG-primed mice over 90 weeks against M. tuberculosis infection. Our findings provided in vivo experimental evidence that rBCG-DisA with c-di-AMP as endogenous adjuvant induced enhanced trained immunity and adaptive immunity. What’s more, rBCG-DisA showed promising potential in prime-boost strategy against M. tuberculosis infection in adults.

Mitochondrial Dysfunction Was Involved in Decabromodiphenyl Ethane-Induced Glucolipid Metabolism Disorders and Neurotoxicity in Zebrafish Larvae

“…A UPLC-ESI-Q-Orbitrap-MS system (UHPLC, Shimadzu Nexera X2 LC-30AD, Shimadzu, Japan) coupled with Q-Exactive Plus (Thermo Scientific, San Jose, USA) was used to perform LC–MS/MS analyses. The specific elution conditions and parameter settings were similar to those in a previous study . The raw MS data were processed using MS-DIAL (RIKEN, Yokohama, Japan) for peak alignment, retention time correction, and peak area extraction.…”

“…The specific elution conditions and parameter settings were similar to those in a previous study. 32 The raw MS data were processed using MS-DIAL (RIKEN, Yokohama, Japan) for peak alignment, retention time correction, and peak area extraction. The metabolites were identified by accuracy mass (mass tolerance <0.01 Da) and MS/MS data (mass tolerance <0.02 Da), which were matched with the Human Metabolome Database (HMDB), MassBank, and a self-built metabolite standard library that was generated by Shanghai Bioprofile Biological Technology Co., Ltd. For the extracted data, only the variables having more than 50% of the nonzero measurement values in at least one group were kept.…”

Cyclic di-AMP Rescues Porphyromonas gingivalis–Aggravated Atherosclerosis

“…Cytokine activation in ApoE −/− mice treated with c-di-AMP for 1 mo resulted in an enhanced response to subsequent Pg infection with long-term effects such as downregulation of inflammatory cytokines and remission of diseases. Therefore, c-di-AMP is widely recognized as an immune adjuvant in cancer immunotherapy and treatment of microbiota infections (Fisher et al 2017; Jiang et al 2020; Leventhal et al 2020; Ning et al 2022; Singh et al 2022). Although the therapeutic potential of c-di-AMP in tumor immunity has been extensively studied, the potential application and underlying mechanisms of c-di-AMP in atherosclerosis treatment remain to be determined.…”

Fighting Tuberculosis: In Search of a BCG Replacement

“…On the one hand, increased c-di-AMP levels have been shown to be associated with the attenuation of Mtb virulence [ 75 ]. On the other hand, a later recombinant BCG strain with c-di-AMP overexpression demonstrated an enhanced immune response as well as a longer-lasting effect in a mouse model [ 76 , 77 ]. This is associated with a c-di-AMP-mediated increase in type I IFN production [ 78 ].…”