Trained immunity in tuberculosis infection: a systematic review
Abstract
Tuberculosis (TB) is considered a major contributor to death resulting from pathogenic bacteria; specifically, Mycobacterium tuberculosis (Mtb) spreads through droplets from individuals with active TB. Both the innate and adaptive immune systems collaborate to control the infection, with innate immunity potentially playing a role in eliminating Mtb. Vaccination, early diagnosis, and treatment can reduce the severity of the infection, but new strategies are still needed to address TB. Research suggests that trained immunity may assist in combating pathogens, including Mtb, and could open new opportunities for treatment. A systematic review was conducted following the eight-step Cochrane methodology and adhering to PRISMA guidelines. An initial automated search identified 157 articles published between 2020 and 2025. Following duplicate removal and evaluation of titles and abstracts, 92 articles remained. After further screening, 52 articles were excluded, and 40 articles were identified for in-depth review. As a result, 8 publications satisfied all eligibility standards and were incorporated into the systematic review. Vaccines (e.g., BCG and TB-MAPS) and adjuvants (e.g., β-glucan) exploit trained immunity to enhance protection. BCG reprograms hematopoietic stem cells (HSCs) via chromatin remodeling, inducing long-term functional alterations in neutrophils, monocytes, and macrophages through epigenetic modifications (e.g., H3K4me3). TB-MAPS generated strong, long-lasting T cell and antibody responses and protected against Mtb infection in both lungs and spleen, matching BCG efficacy. When combined with BCG, it showed synergistic effects, further lowering lung bacterial load. Protection relied partly on IL-12p40 signaling, with IFN-γ and IL-17A pathways driving systemic and lung immunity. β-glucan operates via IL-1 signaling, epigenetically upregulating IL-1 family genes and enhancing proinflammatory responses via the PI3K/Akt/mTOR pathway. These interventions boost myelopoiesis and strengthen both innate and adaptive immune memory, providing stronger protection against TB and opening avenues for new therapeutic approaches.
References
Zhou J, Lv J, Carlson C, Liu H, Wang H, Xu T, et al. Trained immunity contributes to the prevention of Mycobacterium tuberculosis infection, a novel role of autophagy. Emerg Microbes Infect 2021; 10(1):578-88.
https://doi.org/10.1080/22221751.2021.1899771
Carabalí-Isajar ML, Rodríguez-Bejarano OH, Amado T, Patarroyo MA, Izquierdo MA, Lutz JR, et al. Clinical manifestations and immune response to tuberculosis. World J Microbiol Biotechnol 2023; 39(8):206.
https://doi.org/10.1007/s11274-023-03636-x
Koeken VA, Verrall AJ, Netea MG, Hill PC, van Crevel R. Trained innate immunity and resistance to Mycobacterium tuberculosis infection. Clin Microbiol Infect 2019; 25(12):1468-72.
https://doi.org/10.1016/j.cmi.2019.02.015
Assefa M, Girmay G. Mycobacterium tuberculosis Biofilms: Immune Responses, Role in TB Pathology, and Potential Treatment. Immunotargets Ther 2024; 31:335-42.
https://doi.org/10.2147/ITT.S455744
TBC Indonesia. Peringatan Hari Tuberkulosis Sedunia 2024: Gerakan Indonesia Akhiri Tuberkulosis (GIAT) [Internet]. 2024 Mar 24 [cited 2026 Apr 19]. Available from: https://tbindonesia.or.id/peringatan-hari-tuberkulosis-sedunia-2024-gerakan-indonesia-akhiri-tuberkulosis-giat/
Arneth B. Trained innate immunity. Immunol Res 2021; 69(1):1-7.
https://doi.org/10.1007/s12026-021-09170-y
Lerm M, Netea MG. Trained immunity: a new avenue for tuberculosis vaccine development. J Intern Med 2016; 279(4):337-46.
https://doi.org/10.1111/joim.12449
Verrall AJ, Schneider M, Alisjahbana B, Apriani L, van Laarhoven A, Koeken VA, et al. Early clearance of Mycobacterium tuberculosis is associated with increased innate immune responses. J Infect Dis 2020; 221(8):1342-50.
https://doi.org/10.1093/infdis/jiz147
Moorlag SJCFM, Khan N, Novakovic B, Kaufmann E, Jansen T, van Crevel R, et al. β-Glucan induces protective trained immunity against Mycobacterium tuberculosis infection: a key role for IL-1. Cell Rep 2020; 31(7):107636. https://doi.org/10.1016/j.celrep.2020.107634
Verrall AJ, Alisjahbana B, Apriani L, Novianty N, Nurani AC, van Laarhoven A, et al. Early clearance of Mycobacterium tuberculosis: the INFECT case contact cohort study in Indonesia. J Infect Dis 2020; 221(8):1351-60.
https://doi.org/10.1093/infdis/jiz168
Khan N, Downey J, Sanz J, Kaufmann E, Blankenhaus B, Pacis A, et al. M. tuberculosis reprograms hematopoietic stem cells to limit myelopoiesis and impair trained immunity. Cell 2020; 183(3):752-70.e22.
https://doi.org/10.1016/j.cell.2020.09.062
Moorlag SJ, Rodriguez-Rosales YA, Gillard J, Fanucchi S, Theunissen K, Novakovic B, et al. BCG vaccination induces long-term functional reprogramming of human neutrophils. Cell Rep 2020; 33(7):108387.
https://doi.org/10.1016/j.celrep.2020.108387
Bickett TE, McLean J, Creissen E, Izzo L, Hagan C, Izzo AJ, et al. Characterizing the BCG induced macrophage and neutrophil mechanisms for defense against Mycobacterium tuberculosis. Front Immunol. 2020; 11:1202.
https://doi.org/10.3389/fimmu.2020.01202
O’Hara JM, Wakabayashi S, Siddiqi N, Cheung E, Babunovic GH, Thompson CM, et al. A MAPS vaccine induces multipronged systemic and tissue-resident cellular responses and protects mice against Mycobacterium tuberculosis. mBio. 2023; 14(1):e03611-22.
https://doi.org/10.1128/mbio.03611-22
Sun SJ, Aguirre-Gamboa R, de Bree LC, Sanz J, Dumaine A, Joosten LA, et al. BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses. Immunity 2024; 57(9):2095-2107.e8.
https://doi.org/10.1016/j.immuni.2024.07.021
Braian C, Karlsson L, Das J, Lerm M. Selected β-glucans act as immune-training agents by improving anti-mycobacterial activity in human macrophages: a pilot study. J Innate Immun 2023; 15(1):751-64.
