{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T10:57:11Z","timestamp":1785495431759,"version":"3.56.0"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Bacillus Calmette-Gu\u00e9rin (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 <jats:italic>Mycobacterium tuberculosis<\/jats:italic> DisA, and found that rBCG-DisA induced enhanced immune responses by subcutaneous route in mice after <jats:italic>M. tuberculosis<\/jats:italic> 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 <jats:italic>M. tuberculosis<\/jats:italic> 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 <jats:italic>M. tuberculosis<\/jats:italic> infection. It was found that rBCG-DisA resided longer than BCG in the lung of <jats:italic>M. tuberculosis<\/jats:italic> 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 <jats:italic>M. tuberculosis<\/jats:italic> infection. Our findings provided <jats:italic>in vivo<\/jats:italic> experimental evidence that rBCG-DisA with c-di-AMP as endogenous adjuvant induced enhanced trained immunity and adaptive immunity. What\u2019s more, rBCG-DisA showed promising potential in prime-boost strategy against <jats:italic>M. tuberculosis<\/jats:italic> infection in adults.<\/jats:p>","DOI":"10.3389\/fimmu.2022.943667","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T06:28:36Z","timestamp":1661236116000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in 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