Rasiani S, et al.
Trained immunity in tuberculosis.
Trained immunity in tuberculosis infection: a systematic review Salma Rasiani1.
Beti Ernawati Dewi1,2.
Febriana Catur Iswanti1,3 MasterAos Programme in Biomedical Sciences.
Faculty of Medicine.
Universitas Indonesia.
Jakarta.
Indonesia, 2Department of Microbiology.
Faculty of Medicine.
Universitas Indonesia.
Jakarta.
Indonesia, 3Department of Biochemistry & Molecular Biology.
Faculty of Medicine Universitas Indonesia https://doi.
org/10.
22146/inajbcs.
ABSTRACT
Submitted: 2025-11-18 Accepted : 2026-03-26 Tuberculosis (TB) is considered a major contributor to death resulting from pathogenic bacteria.
Mycobacterium tuberculosis (Mt.
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 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 As a result, 8 publications satisfied all eligibility standards and were incorporated into the systematic review.
Vaccines .
BCG and TB-MAPS) and adjuvants .
, -gluca.
exploit trained immunity to enhance protection.
BCG
reprograms hematopoietic stem cells (HSC.
via chromatin remodeling, inducing long-term functional alterations in neutrophils, monocytes, and macrophages through epigenetic modifications .
H3K4me.
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- and IL-17A pathways driving systemic and lung immunity.
-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.
ABSTRAK
Keywords:
adaptive immune innate immune Mycobacterium trained Immunity Tuberkulosis (TB) dianggap sebagai kontributor utama kematian akibat bakteri patogen, terutama Mycobacterium tuberculosis (Mt.
, yang ditularkan melalui droplet dari penderita TB aktif.
Sistem imun bawaan dan adaptif bekerja bersama untuk mengendalikan infeksi, dengan imunitas bawaan memiliki potensi untuk membantu menghilangkan Mtb.
Vaksinasi, diagnosis yang cepat, dan pengobatan yang tepat dapat mengurangi keparahan infeksi, namun masih dibutuhkan strategi baru untuk mengatasi TB secara lebih efektif.
Penelitian terkini menunjukkan bahwa trained immunity berperan dalam membersihkan patogen, termasuk Mtb, dan pemahaman lebih dalam mengenai mekanisme ini dapat membuka peluang baru dalam pengobatan TB.
Sebuah tinjauan sistematis dilakukan dengan mengikuti metodologi delapan langkah Cochrane dan mematuhi pedoman PRISMA.
Pencarian otomatis awal mengidentifikasi 157 artikel yang diterbitkan antara tahun 2020 dan 2025.
Setelah menghapus duplikat dan menyaring judul serta abstrak, tersisa 92 artikel.
Setelah proses penyaringan lebih lanjut, 52 artikel dikeluarkan, menyisakan 40 artikel untuk tinjauan teks Akhirnya, 8 artikel memenuhi semua kriteria inklusi dan dimasukkan dalam tinjauan sistematis, sementara 32 artikel dikeluarkan.
Vaksinasi (BCG dan TB-MAPS) serta adjuvan (-gluka.
, dapat meningkatkan perlindungan melalui trained immunity.
BCG memprogram ulang hematopoietic stem cell (HSC) melalui perombakan kromatin, sehingga memicu perubahan fungsi jangka *corresponding author: febriana.
iswanti@ui.
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panjang pada neutrofil, monosit, dan makrofag melalui modifikasi epigenetik (H3K4me.
TB-MAPS menghasilkan respons sel T dan antibodi yang kuat serta tahan lama, dan mampu memberikan perlindungan terhadap infeksi Mtb pada paru-paru dan limpa, dengan efektivitas setara BCG.
Ketika dikombinasikan dengan BCG, efeknya bersifat sinergis sehingga semakin menurunkan jumlah bakteri di paru.
Perlindungan sebagian bergantung pada sinyal IL-12p40, dengan jalur IFN- dan IL-17A yang mendorong kekebalan sistemik dan paru.
-glukan bekerja melalui sinyal IL-1, secara epigenetik meningkatkan ekspresi gen keluarga IL-1 dan memperkuat respons proinflamasi melalui jalur PI3K/ Akt/mTOR.
Intervensi ini meningkatkan mielopoiesis dan memperkuat memori imun bawaan serta adaptif, memberikan perlindungan yang lebih kuat terhadap TB dan membuka peluang untuk pendekatan terapeutik baru.
INTRODUCTION
Tuberculosis (TB).
Mycobacterium tuberculosis (Mt.
, is a leading cause of death from pathogenic 1 Primarily affecting the lungs.
Mtb spreads from the initial infection site to other organs via airborne droplets from active cases.
2,3 In 2021, the WHO 6 million cases .
6 million deaths, with Southeast Asia .
%).
Africa .
%), and the Western Pacific .
%) being the most affected regions.
Drug-resistant cases rose by 3%, including 450,000 rifampicinresistant cases.
4 By 2023.
Indonesia ranked second globally with 1,060,000 cases and 134,000 deaths.
Multicellular organisms rely on innate and adaptive immunity for Innate immunity forms the first line of defense against Mtb before host cell infiltration, while adaptive immunity, which works alongside it, recognizes non-self structures via humoral/cellular components.
6 Although adaptive immunity typically controls Mtb infection, innate systems can also eliminate it.
Traditionally, responds promptly but non-specifically, lacking memory cells to prevent However, pattern recognition receptors (PRR.
enable recognition, and reinfection enhances responses in humans and other species, leading to Autrained immunityAy.
6 Though adaptive immunity controls Mtb infection, innate mechanisms can eradicate the pathogen, as evidenced by Indonesian contacts who exhibited resolving innate responses and heightened heterologous cytokines production before IGRA conversion.
This involves innate immune memory developed via metabolic and epigenetic changes, which improve responses to secondary infections.
Vaccination, early diagnosis, and treatment reduce TB severity, yet persistent infections demand new Despite advances in TB biology over the past decade, standard 6-month regimens .
sing 2-4 antibiotic.
, as well as the need for better vaccines and shorter therapies, remain critical since outcomes have not sufficiently improved.
7 Trained immunity plays a pivotal role in Mtb clearance and inflammation and the modulation of inflammation.
1 Deeper mechanistic insights could yield novel Thus, this review explores trained immunity within the innate immune system based on prior studies.
MATERIAL AND METHODS
This study used a systematic review A systematic review is an approach for conducting research that incorporates an in-depth assessment of Rasiani S, et al.
Trained immunity in tuberculosis.
all relevant scientific literature related to the research topic in order to provide a comprehensive summary.
The process of searching and writing this article adhered to the preferred reporting items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
An extensive utilizing various databases, including SCOPUS.
PubMed, and Semantic Scholar.
The database searches were performed between February to March 2025 to compile the most comprehensive list of relevant studies.
We specifically focused on articles related to trained immunity in tuberculosis infection.
Clear and spesific keywords string were applied at each stage of the search, including: (AuTrained ImmunityA.
(AuMycobacterium TuberculosisAy AND AuTuberculosis InfectionA.
and (AuImmunityAy AND AuImmunologyA.
OR (AuTuberculosisA.
The inclusion criteria for this review encompassed articles that specifically addressed trained immunity in tuberculosis infection, were published in scientific journals as full papers, were open access, and written in English.
Only studies published in the past five years .
0Ae2.
were considered.
Gray literature or publications not meeting these criteria were excluded.
To ensure a rigorous and unbiased selection process, study screening was performed independently by two The screening was conducted in two successive stages: title-andabstract screening and full-text review.
During the first stage, both revieweres independently screened the titles and abstracts of all identified records against the predefined eligibility criteria based on the PICO framework.
Following the initial screening of titles and abstracts, retrieved in full and independently assessed for final inclusion.
RESULT
Study selection The selection and data extraction process followed the Cochrane eight-step methodology and adhered to PRISMA An initial automated search identified 157 articles published between 2020 and 2025.
Following duplicate removal and evaluation of titles and abstracts, 92 articles remained.
Following a further screening process, 52 articles were excluded, leaving 40 articles for full-text review.
As a result, 8 publications satisfied all eligibility standards and were incorporated into the systematic review, while 32 articles were excluded (FIGURE Any discrepancies or disagreements between the two reviewers regarding study eligibility were resolved through collaborative discussion.
In cases where a consensus could not be reached, an academic supervisor was consulted to make the final determination.
This process was managed using Covidence to ensure inter-rater reliability throughout the study selection phase.
Our systematic review employed multi-stage methodology to identify relevant literature for analysis.
Beginning with an initial cohort of 157 publications database searches, we progressively refined our selection through structured identification and screening phases.
Each record underwent careful evaluation against predefined inclusion and exclusion criteria, followed by detailed full-text assessment of potentially eligible studies.
This meticulous process ultimately yielded 8 pertinent studies that met our stringent quality standards and relevance requirements, ensuring a focused and reliable evidence base for our synthesis.
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Screening Identification Trained Immunity in Tuberculosis Infection Review Records removed before screening:
Duplicate records removed .
= .
Records marked as ineligible by automation tools .
= .
Records removed for other reasons .
= .
Records identified from (PubMed.
Scopus.
Semanti.
= .
Records screened .
= .
Records excluded** .
= .
Reports sought for retrieval .
= .
Reports not retrieved .
= .
Included Reports assessed for eligibility .
= .
Reports excluded .
= .
Reason 1: Review .
= .
Reason 2: Wrong Setting .
= .
Reason 3: Wrong Outcomes .
= .
Reason 4: Wrong Comparator .
= .
Reason 5: Wrong Indication .
= .
Reason 6: Systematics Review .
= .
Reason 7: Wrong Intervention .
= .
Reason 8: Wrong Study Design .
= .
Studies included in review .
= .
FIGURE 1.
Method of Screening TABLE 1.
Summary of selected study .
= .
Author Objective Type of Subject Result Moorlag SJ This study explores how -glucan In vivo.
In exposure reprograms monocytes and vitro macrophages to enhance long-term antimicrobial defense against Mtb.
Using human and mouse models, it investigates cytokine production, gene expression, and IL-1Aemediated myelopoiesis as key mechanisms of trained immunity.
Human.
Mice Verrall AJ et.
,10
This study investigates factors linked In vivo to early clearance of Mycobacterium tuberculosis (Mt.
among household contacts of TB patients in Indonesia.
Human -glucan triggered epigenetic changes in monocytes, boosting IL-6.
TNF, and IL1 production and reducing Mtb growth.
In mice, it improved survival and lung protection by expanding myeloid These effects depended on IL-1 signaling, proving its essential role in -glucanAeinduced trained immunity.
About 25% of contacts showed early clearance by remaining IGRA negative.
BCG vaccination significantly reduced infection risk, though its protection weakened with age and exposure.
Higher hemoglobin, lymphocyte, and monocyte counts increased infection odds, while neutrophils had a slight protective effect, highlighting both immune and metabolic factors in TB resistance.
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Trained immunity in tuberculosis.
TABLE 1.
Cont.
Author Objective Type of Subject Result Mtb reprograms HSCs via a type I IFN/ iron axis, suppressing myelopoiesis and trained immunity through RIPK3dependent necroptosis.
This impairs macrophage function and antimicrobial In contrast.
BCG promotes protective immunity via IFN-II and IL-1 pathways, highlighting MtbAos immune evasion strategy and BCGAos long-term immune benefits.
Khan N et.
,11
This how In vivo.
Mycobacterium tuberculosis (Mt.
In vitro and BCG vaccination differently affect hematopoietic stem cells (HSC.
in the bone marrow.
Using mouse models and RNA sequencing, it examines how each influences immune training, focusing on cytokine signaling, iron metabolism, and cell death pathways.
Mice Moorlag SJ ,12 This study explores how the BCG In vivo, vaccine, known for tuberculosis In vitro prevention, also induces long-term immune reprogramming in human Researchers assessed changes in neutrophil phenotype, function, metabolism, and epigenetics in vaccinated individuals over a 3-month period Human.
BCG vaccination led to enhanced Mice neutrophil activation, greater pathogenkilling ability, increased cytokine and ROS production, and metabolic shifts .
igher These effects were supported by epigenetic modifications (H3K4me.
and upregulation of lncRNAs, indicating trained immunity that strengthens neutrophil response to infections Bickett TE
,13
This study examines whether early.
In vivo T cell-independent innate immunity contributes to BCGAos protection against pulmonary tuberculosis.
Using various mouse knockout models and cell depletion techniques, researchers assessed lung immune cell recruitment and cytokine responses after BCG vaccination.
Mice BCG reduced mycobacterial burden within 7 days, even without CD4/CD8 T cells or TNF-, indicating innate-driven Monocytes, macrophages, and neutrophils played key roles, with live BCG required for full efficacy.
Protection was independent of NOD2 signaling, highlighting a unique, rapid innate immune mechanism.
OAoHara JM
,14
This study introduces TB-MAPS, a In vivo multivalent TB vaccine combining Mtb protein antigens on biotinylated Researchers tested its ability alone and with BCG to induce broad, durable immune responses in mice, focusing on T cell diversity, antibody production, and memory across systemic and lung Mice 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 Protection relied partly on IL-12p40 signaling, with IFN- and IL-17A pathways driving systemic and lung immunity.
Sun SJ et.
,15
This study analyzes how BCG In vivo vaccination affects human bone marrow at the epigenetic and transcriptional levels.
Using scRNAseq and scATAC-seq, researchers examined changes in hematopoietic stem and progenitor cells (HSPC.
from vaccinated individuals to understand how BCG drives longterm immune reprogramming.
Human BCG induced lasting gene expression and chromatin changes in HSPCs, especially in hematopoietic stem cells and megakaryocyte-erythroid These changes favored immune and metabolic pathways, with over 13,000 enhanced IL-1 and IL-6 secretion upon fungal challenge, indicating stronger innate immune responses.
Braian C et.
,16
This whether In vitro different -glucans can train human macrophages to enhance their ability to control M.
tuberculosis growth.
Human monocytes were trained with -glucans from various sources, and macrophage function, cytokine epigenetic changes were analyzed.
Human Training with curdlan and Alternariaderived -glucans improved macrophage control of M.
tuberculosis, boosting IL-6 and IL-1 production.
WGP dispersible -glucan showed mixed responses among Neutrophil co-culture enhanced of -glucan type.
Epigenetic analysis -glucan-induced in immune-related gene methylation, highlighting IL-6 as a key marker of improved mycobacterial defense.
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Epigenetic immune activation by -glucan According to a study by Moorlag SJ et al.
,9 -glucan AutrainingAy of human monocytes resulted in epigenetic modifications and the upregulation of genes involved in anti-mycobacterial defense, leading to increased production of IL-6.
TNF, and IL-1, as well as the inhibition of Mtb growth upon exposure.
-glucan significantly reduced the pulmonary Mtb burden and improved survival rates.
These protective effects were associated with the expansion of hematopoietic stem cells and myeloid progenitors in the bone marrow.
Importantly, the protective benefits of -glucan were lost in IL-1 receptorAedeficient mice or after IL-1 inhibition, confirming the necessity of IL-1 signaling for trained immunity and protective myeloid cell development against Mtb infection.
Braian C et al.
,16 evaluated whether different -glucans can train human macrophages to enhance their ability to control M.
tuberculosis growth.
The study found that training macrophages with curdlan and Alternaria-derived -glucans macrophage control of M.
growth compared to untrained controls, production of IL-6 and IL-1 cytokines.
WGP dispersible -glucan showed variability among donors, dividing them into AurespondersAy .
ith enhanced mycobacterial control and higher IL-6 releas.
and Aunon-responders.
Ay The co-culture of neutrophils and macrophages further enhanced control of mycobacterial growth, although this effect was not dependent on the -glucan Epigenetic analysis revealed that -glucan training led to differential methylation of genes linked to immune interferongamma signaling in WGP responders and interleukin/cytokine signaling in curdlan- and Alternaria-trained cells.
The study provides evidence that certain -glucans can act as immune trainers, boosting macrophage responses against tuberculosis through functional and cytokine production .
specially IL-.
emerging as a key correlate of improved anti-mycobacterial activity.
Impact of BCG vaccination on IGRA positivity and infection risk Among 1347 contacts of TB cases, 9% were IGRA positive and 36.
were negative at baseline.
After 14 weeks, 26.
1% of initially negative contacts became IGRA converters, while 2% remained persistently negative and were classified as Auearly clearers.
Ay Notably.
BCG vaccination substantially reduced the likelihood of both baseline IGRA positivity and IGRA conversion after exposure, with the protective effect decreasing as both Mtb exposure and age Early clearers, who accounted for about a quarter of all contacts had lower measures of exposure and tended to be younger.
Higher hemoglobin concentration was associated with a greater risk of IGRA conversion.
The findings highlight that BCG vaccination offers significant but variable protection against Mtb infection, influenced by the degree of exposure and age, underscoring the need for new vaccine strategies that enhance early clearance mechanisms.
According to the findings reported by Moorlag SJ et al,12 BCG vaccination led to enhanced neutrophil activation, pathogen-killing increased cytokine and ROS production, and metabolic shifts .
owards higher These effects were supported by epigenetic modifications (H3K4me.
and the upregulation of lncRNAs, indicating trained immunity that strengthens neutrophil response to On the other hand a study by Rasiani S, et al.
Trained immunity in tuberculosis.
Bickett TE et al.
,13 demonstrated that.
BCG vaccination produced a significant reduction in Mycobacterium tuberculosis burden as early as 7 days post-vaccination, even in the absence of conventional T cells (CD4.
CD.
or TNF-, indicating strong, rapid innate immunity.
Lung the recruitment of CD11b F4/80 monocytes/macrophages increase in neutrophils in vaccinated Functional experiments showed that depletion of neutrophils prior to and during vaccination decreased the protective effect, confirming their role in establishing early immunity.
Importantly, live BCG was required for maximal mycobacterial killing.
-irradiated BCG, while still stimulating macrophage cytokine production, was less effective in reducing bacterial burden.
Protective effects were not dependent on NOD2mediated trained immunity or the vaccineAos route of administration .
xcept for low dose aeroso.
, emphasizing an alternative, unconventional mechanism where monocytes, macrophages, and neutrophils function together to induce rapid early mycobacterial clearance following BCG vaccination.
The study by Sun SJ et al.
,14 found that BCG vaccination induces significant and lasting changes in both gene expression and chromatin accessibility within HSPCs.
At the transcriptional level, the strongest effects appeared in the most uncommitted hematopoietic stem cells (HSC.
and megakaryocyteerythroid progenitors (MEP.
, with hundreds of differentially regulated genes detected 90 days post-vaccination.
These genes were enriched in immune, metabolic, and proliferative pathways, with HSCs showing persistent rewiring suggestive of a myeloid lineage bias.
At the epigenetic level, over 13,000 regions were identified, predominantly in more differentiated progenitors such as CMPs .
ommon myeloid progenitor.
and GMPs .
ranulocytemonocyte progenitor.
Importantly, transcription factor motifs enriched in these progenitors overlapped with transcription factors activated in HSCs, suggesting a cascade from stem cells to downstream lineages.
Functionally, these molecular changes correlated strongly with increased secretion of IL-1 and IL-6 by PBMCs upon fungal challenge.
BCG reprograms bone marrow stem cells in a way that enhances peripheral innate immune responses.
Mtb-induced IFN-I suppresses myelopoiesis in HSCs A study by Khan N et al.
,10
demonstrates that, unlike BCG or -glucan.
Mtb reprograms hematopoietic stem cells (HSC.
through a type I interferon
(IFN-I)
suppresses myelopoiesis and disrupts the development of protective trained Mechanistically.
Mtb-induced IFN-I signaling leads to dysregulation of iron metabolism, depolarization of mitochondrial membrane potential.
RIPK3-dependent specifically in myeloid progenitors.
This results in the depletion of myeloid progenitors, a failure to produce effective macrophages, and ultimately, a compromised innate immune response to Mtb infection in vivo.
Both intravenous and physiological aerosol infection with Mtb led to rapid dissemination into the bone marrow, persistent alteration of HSC function, and long-term reduction of hematopoietic output for at least one year.
These detrimental changes in HSC function are contrasted by the beneficial reprogramming and enhanced with BCG vaccination, which biases hematopoiesis toward myelopoiesis and supports trained immunity.
Loss of iron homeostasis further exacerbates susceptibility to Mtb infection, while InaJBCS.
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BCG or -glucan imprinting is associated with preserved myelopoiesis and robust anti-TB immune responses.
TB-MAPS:
vaccination strategies TB-MAPS vaccination induced strong, long-lived antigen-specific antibody responses and a large repertoire of memory T cell subsets, including Th1.
Th17, cytotoxic CD4 and CD8 cells, as well as functionally diverse T cells and NKT cells in both systemic circulation and respiratory tissues.
In mouse aerosol challenge models.
TB-MAPS alone provided protection against both lung and spleen infection comparable to BCG, reducing bacterial loads by approximately 4- to 10-fold relative to controls.
Importantly, concurrent or sequential administration of TBMAPS with BCG produced synergistic effects, achieving up to an additional 8-fold reduction in lung bacterial burden compared to either vaccine alone while maintaining protection in the spleen.
The vaccineAos cellular responses were partially dependent on the IL-12p40 pathway, with IFN-mediated (Th.
protection crucial for controlling dissemination, while IL17A-associated lung protection involved both IL-23-dependent and -independent mechanisms .
ncluding T and NKT
DISCUSSION
The collected evidence from the reviewed studies demonstrates that both Mycobacterium tuberculosis (Mt.
infection and Bacillus Calmette-Guyrin (BCG) vaccination produce significant and durable effects on hematopoietic and innate immune reprogramming.
BCG vaccination consistently activates hematopoietic stem and progenitor cells, leading to enhanced myelopoiesis, longlasting trained immunity phenotypes in monocytes and neutrophils, and an improved capacity to control Mtb and unrelated pathogens, as shown in both experimental and clinical 10-12,14-17 In contrast.
Mtb infection subverts immunity by epigenetically and metabolically suppressing myeloid cell development and impairing the establishment of protective trained immunity, a process that exploits type I interferon signaling and iron The introduction of innovative vaccine designs, including the MAPS platform, further expands the induction of systemic and tissue-resident cellular memory, yielding potent protection in preclinical models.
14 However, the predominantly preclinical nature of MAPS data, especially in murine models, still limits direct inference to human populations and highlights the need for cautious interpretation.
Together, these studies provide strong evidence that innate immune memory, or trained immunity, extends beyond monocytes to involve neutrophils tissue-resident 12,16 The findings from the INFECT study in Indonesia, highlight the real-world impact of early clearance and prevention of Mtb infection, which appears to be closely linked to mechanisms of innate protection stimulated by BCG.
10 Nonetheless, the human studies summarized in this review are often constrained by relatively small sample sizes and substantial inter-individual .
variability in immune responses, which may lead to overestimation or underestimation of effect sizes and limit generalizability to broader TBendemic Mechanistic investigations of BCG and -glucans converge on the discovery of epigenetic, metabolic, and transcriptional rewiring in innate immune cell lineages, providing an expanded view of vaccine-induced immunity across human and animal 10,11,16 In -glucan studies in particular.
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Trained immunity in tuberculosis.
heterogeneity between donors, including genetic background, prior infections, and comorbidities, introduces additional noise that needs to be acknowledged as a source of potential bias when interpreting trained immunity readouts.
These articles are notable for their methodological strengths, such as the application of single-cell sequencing, protocols, and translational animal studies, yielding detailed insights into cell fate and gene expression signatures following BCG and Mtb exposure.
However, certain limitations persist, including variability in individual immune responses, the challenge of differentiating durable from transient changes in stem cell populations, and the limited duration and sample sizes in many studies.
10,14,15 Small human cohorts and short followup periods are especially important constraints for drawing firm conclusions about longterm persistence and clinical relevance of trained immunity.
The interpretation of field epidemiology data is complicated by confounders such as BCG scar misclassification or exposure intensity among participants, as highlighted by Verrall et al.
,10 and at a mechanistic level, there is a need for further clarification of the link between stem cell programming and adaptive immunity.
10,15 Moreover, the heavy reliance on murine models, while mechanistically informative, is intrinsically limited by speciesspecific granulopoiesis, and TB pathogenesis, which may not fully recapitulate human When considered together, these design features also raise the possibility of publication bias, where positive or mechanistically appealing findings are more likely to be reported than neutral or negative studies, potentially skewing the apparent strength of evidence in favor of trained immunitybased interventions.
Despite these challenges, the evidence strongly argues for the continued prioritization of BCG vaccination and the development of interventions that harness trained immunity for TB prevention.
Demonstrations that -glucans and novel subunit vaccines, such as MAPS, can induce similar directions for TB immunotherapy.
These strategies have the potential not only to reduce tuberculosis risk but also to improve host broadly protective 10,14,16 Translationally, these observations are particularly relevant for TB contact management, where trained immunity inducing approaches could, in principle, complement existing preventive strategies .
uch as TPT) to enhance early control of Mtb in recently exposed household and community At the programmatic level, national vaccine programs would require alignment with current BCG policies, consideration of booster or adjunct schedules, costeffectiveness in highburden settings, and compatibility with existing childhood and adult immunization platforms.
For MAPSbased or glucanAebased interventions, issues of safety, route of administration, dosing, and manufacturability will be critical determinants of feasibility for largescale implementation in humans.
Mechanistic data reveal that trained immunity from BCG and -glucans results from deep-layered epigenomic modifications, such as histone H3K4me3 methylation, metabolic shifts favoring glycolysis, and transcription factor activation, all of which shape the phenotype and function of both stem and mature innate immune cells.
9,12,15,16
In contrast.
Mtb manipulates host immunity by suppressing myelopoiesis through the interferon and iron axis, resulting in programmed cell death of progenitors and failure to establish These mechanistic contrasts offer a biological rationale for prioritizing interventions that reinforce beneficial myelopoiesis and trained innate responses, but they InaJBCS.
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still require validation in sufficiently powered human studies that reflect the diversity of TBexposed populations.
In summary, the integrated review of contemporary mechanistic and epidemiological research underscores the importance of innate immune reprogramming and trained immunity in defending against tuberculosis infection and disease.
The future of TB prevention likely hinges on improved understanding precision vaccine development, and their judicious application in vulnerable, high-burden
10,11,14,16
Strengthening critical appraisal of study design limitations and more clearly articulating the translational pathway from experimental trained immunity to feasible, scalable tools for TB contact management and national vaccination programs will be essential to realize this To elucidate the multifaceted mechanisms of trained immunity contributes to the prevention of tuberculosis infection, a comprehensive illustration is presented (FIGURE .
This schematic illustrates the induced by -glucans.
BCG and TBMAPS vaccines against tuberculosis (TB) The first panel depicts the -glucan triggered epigenetic changes in monocytes, boosting IL-6.
TNF, and IL1 production and reducing Mtb growth.
In mice, it improved survival and lung protection by expanding myeloid The second panel show BCG pathway.
BCG vaccination activates hematopoietic stem and progenitor cells, leading to enhanced myelopoiesis, longlasting trained immunity phenotypes in monocytes, macrophage and neutrophils.
These molecular changes correlated strongly with increased secretion of IL1 and IL-6.
In contrast, the third panel shows TB-MAPS generated strong, longlasting T cell and antibody responses and protected against Mtb infection in both lungs and spleen.
This image was created with BioRender .
ttps://biorender.
FIGURE 2.
Summary of trained immunity mechanisms in tuberculosis infection.
Rasiani S, et al.
Trained immunity in tuberculosis.
This review has several limitations.
Much of the evidence for TB MAPS is preclinical and derived from murine models, which restricts direct extrapolation to humans and requires cautious interpretation.
Human studies are often based on small cohorts, short follow up, and substantial donor variability, particularly in glucan studies, potentially biasing effect estimates and limiting generalizability to TB endemic populations.
The heavy reliance on animal and in vitro models, combined with a likely publication bias favoring positive or mechanistically the strength of support for trained immunityAebased interventions.
Finally, although mechanistic data provide a rationale for targeting trained immunity, key translational aspects including integration with TB contact management and national vaccination programs, as well as the practical feasibility of MAPS and glucanAebased strategies remain insufficiently validated in large, diverse human cohorts.
ACKNOWLEDGMENT
The authors would like to thank Lutvi Abdullah for his invaluable assistance in preparing the methodology for this paper.
REFERENCES