During active state, upon M.tb phagocytosis through toll-like receptors (TLRs), especially TLR2/4, the alveolar macrophages become activated in MyD88 dependent manner which leads to acquiring a pro-inflammatory ‘M1’ phenotype (55). ‘M1’ macrophages require a massive number of ATPs to synthesize pro-inflammatory cytokines such as IL-1β and antimicrobial peptides, therefore these macrophages reprogram the metabolic processes and shift to glycolysis to meet their energy requirements (56). Laura et al., have shown that M.tb induces a metabolic shift towards aerobic glycolysis and perturbs OXPHOS in alveolar macrophages (57). This results in the accumulation of TCA cycle products such as succinate that induces the expression of hypoxia-inducible factor 1α (HIF-1α) (53). HIF-1α is the master regulator of the glycolysis pathway that regulates the expression of glycolytic enzymes which further acts in a positive feedback manner to increase the glycolysis (58). Metabolic plasticity in macrophages has been extensively reviewed elsewhere (53, 59). It has been broadly studied that M.tb induces ‘Warburg effect’ by increasing the expression of glucose receptors that ultimately leads to enhanced uptake of glucose within the infected macrophages (60). This is accompanied by the increase in end- product of glycolysis, i.e., lactate secretion in extracellular spaces. It has been demonstrated that lactate secreted from the infected cells drive the negative regulation of glycolysis in the resting macrophages (61). The decrease in glycolysis is balanced by the increase in OXPHOS, thereby lactate act as immunomodulator by inhibiting the production of IL-1β and TNF. However, it is interesting to note that lactate rewires the metabolic responses in resting macrophages so that subsequent infection with M.tb is diminished (61). Conversely, a recent study suggests that enhanced glucose uptake or during Diabetes Mellitus in TB patients (TB-DM), the increased glucose levels negatively regulate HIF-1α, and thus mediates the survival of M.tb in the infected macrophages (62). Another study demonstrated that alveolar macrophages offer nutrient rich and permissive environment for M.tb and thus enables higher bacterial replication when compared with interstitial macrophages Further sequencing analysis revealed that alveolar macrophages have higher fatty acid oxidation that allows release of fatty acids and cholesterol available for uptake by M.tb (63). Furthermore, M.tb maintains low replicating stage, and sustain in extracellular compartment within the granuloma. This is likely due to low amounts for fatty acids and cholesterol, which are necessary for its replication (64).

Nonetheless, M.tb has evolved key mechanisms to drive the transition from M1 to M2 phenotype by ravaging mitochondrial integrity. M.tb secretes ESAT-6 that damages mitochondrion upon mTOR inhibition, destroys mitochondrial membrane and disrupts the membrane potential (65). This in turn interrupts the contacts between mitochondrion and phagolysosome, which is thought to be necessary for M.tb killing (10.1016/j.micinf.2015.06.003). Another defensive strategy employed by M.tb is delayed apoptosis and enhanced upregulation of OXPHOS in M.tb infected macrophages. Rv1813c is an effector M.tb protein that when overexpressed in macrophages, is deposited in mitochondrial matrix and prevents the release of cytochrome c (6). However, M.tb secretes various potent antigenic proteins that collectively promotes M.tb survival, but their collective role in altering macrophage metabolism is yet to be studied. Also, this has been known for ages that during latent TB, M.tb secretes ESAT-6 in granuloma during latent TB, and simultaneously, macrophages exhibit anti-inflammatory properties (66). However, least efforts have been made to visualize what happens at metabolic level that do not allow the macrophage cell death, even with loss of mitochondrial integrity. Metabolomic analysis of M.tb infected macrophages revealed higher levels of NAD⁺, glutathione and creatinine, and it has been reported that these metabolites collectively regulate anti-mycobacterial activity of macrophages as compared to uninfected macrophages (56). Additionally, M.tb upregulates glutathione metabolism in macrophages resulting in higher levels of glutamine, that supports M2 polarization (67). Recent studies have classified ratios of amino acids in plasma to whole blood as biomarkers with 84% sensitivity in detecting active TB patients. Amino acids such as leucine, asparagine, ornithine, arginine, tyrosine and serine are present in higher ratios in TB patients when compared to cured TB patients and healthy controls (68). These are probably secreted in the blood and are taken up by macrophages for Nitric oxide (NO) production. Conversely, one of the interesting studies suggested that administration of L-tyrosine curbs mycobacterial survival in TB granulomas, possible due to increased production of ROS (69). However, amino acid metabolism in host macrophages is yet to be elucidated with respect to TB progression.

Innate immune cells such as macrophages and DCs bridge the antigen encounter with naïve adaptive immune cells through antigen presentation. M.tb infected M1 macrophages secrete certain cytokines such as IL-6, IL-10, and IL-12 in the local environment where naïve T cells sense these cytokines, and enhance their glycolysis to prompt effector functions (70). Together with this, T cells need to proliferate and expand clonally which necessitates the rapid synthesis of proteins, lipids and DNA. These phenotypes are acquired by rapid nutrient uptake such as glucose, and other metabolites, and calcium mobilization. In accordance to T cell effector functions, ketolysis is an alternative to glycolytic pathway that drives CD8⁺ T cell cytolytic and cytokines functions such as IFN-γ and TNF-α (71). It is relevant to investigate ketolysis in TB progression and to delineate the possible protective mechanisms against TB.

In general, TCR interaction with co-stimulatory molecules such as CD80/86 induces mitochondrial biogenesis, that also enhances the upregulation of AMP kinase, and further supplements ATPs for rapid T cell proliferation and effector functions (72). A remarkable study demonstrated that mitochondrial matrix protein, Cyclophilin D (CypD) controls M.tb infection by controlling T cell responses, and maintains disease tolerance. In CypD deficient M.tb infected mice, there is higher infiltration of T cells in lungs, which leads to lung pathology. The study has established that CypD tightly controls aerobic glycolysis in T cells in ROS dependent manner that is known for inducing effector functions such as production of IFN-γ, TNF-α and IL2 (73). As discussed by Koeken et al., T cells and other myeloid cells are evolving in conjunction with M.tb to promote disease tolerance that eventually leads to lower immunopathology (74).

Nonetheless, chronic exposure of M.tb results in T cell dysfunction, primarily, CD8⁺ T cells. M.tb exposure stems metabolic reprogramming in T cells which subsequently ensues the expression of exhaustion markers such as PD-1, CTLA-4 (75). Through transcriptomic and experimental analysis, these observations are finely correlated with reduced glucose uptake by M.tb specific CD8⁺ T cells. The series of bioenergetics further demonstrated that chronic exposure of CD8⁺ T cells dampens mitochondrial health, declining OXPHOS, and reduced production of cytokines, which marks T cell exhaustion (75). However, CD4⁺ T cells are known to prevent CD8⁺ T cell exhaustion during M.tb infection by an unknown mechanism to produce more IFN-γ, TNF-α, granzymes and perforins (42). Based on these evidences, this could be speculated that CD4⁺ T cells modulate CD8⁺ T cells by preventing mitochondrial dysfunction, and more pronounced aerobic glycolysis. Nonetheless, these aforementioned speculations need experimental validations and analysis. Conventional to the metabolism in all immune cells, HIF1α is known in CD4⁺ T cells to upregulate glycolysis to produce ATP rapidly. This is paramount for release of cytokines such as IFN-γ that drives macrophage activation. Nevertheless, using conditional knockout mechanisms, Liu et al., have shown that deletion of negative regulator of HIF-1α, VHL, dampens the host’s ability to control M.tb infection, and hence lower accumulation of M.tb specific T cells in the lungs of these mice. This is explained by the fact that VHL is vital for stabilizing the appropriate extent of HIF1α in controlling CD4⁺ T cell response against M.tb. This further accompanies to prevent CD4⁺ T cell exhaustion during M.tb infection. Altogether, VHL is required for T cell activation, DNA replication and proliferation (76).

The above- mentioned reports are well described in the context of effector functions of T cells. Conversely, minimal efforts are put into identifying the metabolic reprogramming in stemming the memory responses of T cells, which are crucial for the basis of any therapeutic development. Our group has previously shown that M.tb induces higher expression of specific histone deacetylase (HDACs), such as Sirtuin 2 in CD4⁺ T cells that deacetylates NF-ĸB at lysine 310 which impairs macrophage- CD4⁺ T cells interactions to restrict M.tb growth (77). Recently, the study from our group has discovered that pharmacological inhibition of Sirtuin 2 by AGK2 induces glycolysis by modulating Wnt-β-catenin pathway, that subsequently enhances T-cell stem cell like memory (CD4⁺ T_scm) responses during M.tb infection. This is further complemented by adjunct therapy with BCG as well as DOTS therapy, that results in higher T_scm responses that further give rise to different memory pools and effector T cells (77, 78). Similarly, whole proteomics analysis of Purified protein derivative (PPD⁺⁾ healthy individuals when treated with an immunomodulator, Berberine, showed upregulation of glycolytic pathway along with NOTCH3, that may possibly play role in prompting protective T cell effector function against TB (79).

In conclusion, it is imperative to note that delving into immunometabolism of the host during M.tb infection will help researchers refine the vaccine development. By incorporating insights into the metabolic requirements of immune cells during M.tb infection, researchers can design vaccines that enhance the overall efficacy of the immune response, potentially leading to more successful prevention and treatment strategies for TB.

The upper respiratory tract acts as a gateway to the lower respiratory tract and to the final destination of M.tb colonization- the lung (94). Similarly, metabolites produced by the gut microbiome can reach the lungs through blood (95). Several studies have hypothesized that dysbiosis of the microbiota in the upper respiratory tract, lungs, and gut increases the chances of M.tb primary infection, reinfection, and reactivation of LTBI (96).

Microbiome colonization is initiated post birth in the mucosal sites. In healthy human lungs, resident microbiome belongs to the following phyla- Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Among these, the most prevalent genera have been identified as following- Prevotella, Streptococcus, Veillonella, Fusobacterium, and Haemophilus (97).

Recent literature suggests an alteration in the microbial community of the upper respiratory tract upon infection with TB. The microbial composition is speculated to have a role in the disease progression from healthy to ATB or LTBI. ATB shows enhancement in gram-positive and gram-negative species. Proteobacteria, Bacteroidata, and Bacillota are the most observed phylum while Balutia and Acinoetbacter are the dominant classes in ATB as compared to the Healthy cohort (HC). HCs were observed to have enrichment in the Lacnospiraceae family and the Faecalibacterium genus. Comparative analysis between the HC and LTBI cohort signified the presence of the Kosakonia genus in HC while the Faecalibacterium genus was enriched in LTBI (98).

Prospective cohort studies have indicated the role of the microbial community in predicting the susceptibility to TB. Notably, Healthy Household Contacts (HHCs) who did not acquire LTBI had an elevated relative abundance of Corynebacterium, Dolosigranulum, Cutibacterium, and Staphylococcus. Conversely, in HHCs with established LTBI, the abundance of Corynebacterium, Lawsonella, Paracoccus, Cutibacterium, Dolosigranulum, and Moraxella was notably higher. It is worth mentioning that the bacterial genera Dolosigranulum and Variovax were exclusively found in HC, leading to the conclusion that these genera are integral components of a healthy nasopharyngeal microbiome. Furthermore, in pre-LTBI patients, the absence of Dolosigranulum, coupled with the presence of Rothia and Megasphaera genera, has raised speculation regarding their potential involvement in modulating host immunity and increasing susceptibility to M.tb infection (99).

In a separate investigation led by Botero et al., noteworthy alterations were observed in the bacterial and fungal communities within the oropharynx of TB patients when compared to individuals in good health. The study unveiled a significant increase in the presence of the Ascomycota phylum in TB patients, indicative of fungal diversity shifts. Conversely, the genus Cryptococcus showed a notable decline in abundance within the oropharynx of TB patients. It is crucial to acknowledge that one of the key limitations of this study is the relatively small sample size, which may impact the generalizability of the findings (100).

These findings suggested a resemblance in nasopharyngeal species diversity and composition among HC, ATB, and LTBI groups, shedding light on the intricate interplay between upper respiratory microbiota and TB infection. These studies have however failed to conclusively show an association between bacterial dysbiosis in the nasopharyngeal tract and the chances of acquiring TB or progressing to LTBI.

Most of the studies focussing on studying lung microbiome diversity in TB rely on sputum samples for their downstream analysis (101). Sputum samples are spuriously contaminated with pharyngeal microbiota; thus, the result fails to be a true indicator of the lung microbiome (102). The investigation of the accurate picture of the lung microbiome is hindered by invasive techniques such as bronchioalveolar lavage fluid (BALF) collection and throat swabs (102). These techniques provide a better picture of the lung microbiome than the traditional sputum collection method.

In the pursuit of a deeper understanding of the lung microbiome, Xiao et al., conducted a study that harnessed BALF samples and employed metagenomics to explore microbial enrichment at the species level. Their findings revealed intriguing disparities between the HC and the Untreated Pulmonary TB Group (UTG). Specifically, the HC displayed enrichment in species like Prevotella melaninogenica and Ralstonia pickettii, while the UTG exhibited a heightened presence of S. aureus and Neisseria gonorrhoeae. These outcomes starkly contrast with those reported by Hu et al., in their BALF-based investigation (103).

Another pertinent study conducted by Pérez et al., shed light on differences in alveolar microbiota among patients with pulmonary TB. Their analysis of BALF samples uncovered a reduction in the Streptococcus genus, while concurrently identifying an increase in the abundance of Mycobacterium, Lactobacillus, and Acinetobacter (104). These findings underscore the complexity and variability in lung microbiota profiles associated with pulmonary TB, emphasizing the need for further research to elucidate the underlying factors and implications of these differences. These two studies provide crucial insights into the lung microbiome in TB patients but are severely limited by the patient sample size.

In a comprehensive study by Kang et al., the investigation unearthed distinct characteristics within the airway microbiota that set patients with M.tb infection apart from those without. Notably, a novel genus, Anoxybacillus, exhibited an increased presence in BALF samples. What sets this study apart is its robust patient sample size, which bolsters the need for further exploration to establish a definitive correlation between the prevalence of Anoxybacillus and TB (105).

Similarly, Zhou et al., research delivered significant findings, underscoring the prevalence of the Cupriavidus genus as dominant in TB patients, while Streptococcus emerged as the dominant genus in healthy subjects. Notably, their study was carried out utilizing BALF samples (106). These observations underscore the utility of BALF in uncovering crucial distinctions in lung microbiota between TB patients and healthy individuals, thus emphasizing the potential significance of these findings in understanding TB pathogenesis and treatment strategies. Despite the vast literature available, there are limited studies linking microbiome alteration to functional disease progression.

Xia et al., undertook a study with the objective of establishing a connection between changes in the microbial composition and variations in cytokine levels within BALF and their potential implications in the progression of TB (107). This investigation aimed to elucidate the interplay between microbial alterations and cytokine dynamics, shedding light on their role in the advancement of TB.

Meta-analysis serves as a valuable avenue for reinforcing scientific findings when the available sample size is constrained. These comprehensive studies amalgamate data derived from multiple investigations centered on a common research question, effectively surmounting the limitations posed by small sample sizes. Notably, a meta-analysis conducted by Hong et al., offered intriguing insights by proposing a co-abundance relationship between R. mucilaginosa and A. graevenitzii with M.tb within the lung microbiota of patients with ATB. It is important to acknowledge that this study is bounded by the number of source studies employed and the origin of the microbiota samples used to mimic the lung microbiome. Nonetheless, it introduces the intriguing possibility that the co-occurrence of specific bacterial communities may serve as a valuable indicator of disease progression and hold potential for predicting treatment outcomes (108).

Microbiome in healthy gut harbor around 50 different bacterial phyla with Bacteroidetes and the Firmicutes as the two dominant gut resident phyla (109). TB progression is marked by dysbiosis of resident gut microbiome (110). Several cohort studies undertaken on the Chinese population indicate differences in diversity, composition, and function of gut microbiota in HC vs TB patients. The studies suggested dysbiosis of the gut microbiome in TB patients with a lower abundance of short-chain fatty acid producers namely microbiome genera such as Lachnospiraceae and species - Haemophilus parainfluenzae, Roseburia inulinivorans, and Roseburia hominis. TB patients also show a notable increase in opportunistic pathogens of the genera Enterococcus and Rothia. The studies suggest dysregulated host metabolism such as decrease in the biosynthesis capacity of amino acids and fatty acids and altered carbohydrate metabolism patterns in the gut in TB patients as compared to HC (13). Butyrate, a short-chain fatty acid, is a key metabolic pathway that is downregulated in notably all the cohort studies involving active TB patients (111). Butyrate production is inversely linked with the severity of inflammatory and metabolic diseases (112).

Demographics, geographic characteristics, and antibiotic usage also impact microbial diversity. Cohort studies from Pakistani, Chinese and Indian populations show differential enrichment of gut microbial phyla in healthy and TB patients (113).

In the Chinese cohort phylum Actinobacteria increased while phylum Bacteroidetes diminished in healthy cohort while in TB patients Proteobacteria and Bacteroidates have been notablyenriched. Firmicutes which shows enrichment in the Pakistani cohort significantly diminished in the Chinese cohort. While Firmicutes and Actinobacteria showed relative enhancement in a cohort study in the Indian population (13).

These microbial signatures need further investigation as the majority of the study uses TB and HC which does not provide confirmatory results on how these signatures might differ from non-TB inflammatory diseases (113).

The secondary metabolites, immune signals and microbial remnant produced by gut/lung microbiome can affect the microbiota composition and abundance in a bidirectional fashion termed as the gut lung axis. The resident microbiome composition can dictate the disease progression. Recent murine studies have demonstrated that enriching the murine gut with Lactobacillus can alleviate asthma-like symptoms in mice (114).

Moreover, administration of IPA produced by gut Clostidia species have shown anti-tubercular activity in murine model by targeting trp and Short chain fatty acids (SCFA) biosynthesis in M.tb (115). It is worth noting that patients with ATB often exhibit increased regulatory T cells (Tregs). Interestingly, Faecal transplantation in murine model have shown to bear fruitful results in reducing T reg population and increasing protective cytokines such as IFN-γ/TNF-α (116).

SCFA produced by gut microbiome can enter the circulatory pathway and reach various peripheral organs including bone marrow. Within the bone marrow SCFA can induce differentiation of progenitor macrophage and DC which can then migrate to the lung and thus modulate lung microenvironment (117) ( Figure 2 ). Anaerobic microbiota in the lower airways produce SCFAs, and elevated serum SCFA levels have been linked to the induction of FoxP3-expressing Tregs in BALF lymphocytes. Pulmonary SCFA produced by anaerobic microbiota has also been associated with a decrease in IFN-γ levels in active TB (118, 119).

Metabolites from the gut commensal microbiome have role in steering the abundance and function of non-conventional T cells such as Natural killer T cells (NKT) and Mucosal associated invariant T cells (MAIT). Studies using germ-free mice have shown the complete absence of MAIT cells, thus pointing towards a probable role of microbiota in affecting the abundance of MAIT cells. MAIT cells have been found to play important role in protection against TB (96).

Although there is limited research on the modulation of the gut-lung axis in TB, an intriguing study conducted by Negi et al., in a murine TB model highlights the role of dendritic cell activation by the gut microbiome of TB. This research suggests gut dysbiosis can lead to low mincle expression on lung DC which negatively regulates antimycobacterial T cell activation in the lung. The study suggests restoration of Lactobacillus as a possible measure to augment mincle based DC signaling (120).

Inflammation mediated by IFN-γ expression is crucial for controlling the initial stages of TB progression. Shen et al., revealed possible association of lncRNA-CGB produced by gut Bacteroides fragilis in positively regulating IFN-γ production by epigenetic reprogramming (121). The long-term anti TB treatment is known to induce significant alteration in microbial community. The altered microbiome can impact effective immune responses generation during the treatment (122). Limited literature is available that can explain the mechanism of lung microbiome mediated changes in the gut microbiome composition upon the initiation of colonization of lung by M.tb.

The mechanism linked to generation of optimal vaccine responses in human is a very complex phenomenon. Several intrinsic and extrinsic factors such as age, genetics, nutritional status, pre-existing immunity and comorbidities dictate the nature of generation of vaccine responses (123). Recent studies have demonstrated yet another intrinsic factor of microbiome that can influence vaccine immunogenicity (124). Antibiotics-induced gut microbiome dysbiosis has been linked to diminished immune response generation to vaccination in healthy adults (125). Optimal vaccine-induced antibody response has been linked to the prevalence of gut commensals in diseases such as bacterial diarrhea, influenza, polio, etc (126). Studies using germ free animal models have linked defective Th1/Th2 responses, reduced intraepithelial lymphocytes, reduced antibody generation and a dysregulation in Th17 cell responses to the host microbiome (127).

In the context of TB, study conducted by Nadeem et al., reported gut microbiome dysbiosis as important determinant in dictating BCG vaccine efficacy in TB. The altered microbial community had a decreased prevalence of Bifidobacterium, Lactobacillus and an increased prevalence of Bacteroides. The dysbiosis resulted in decreased activation and frequency of various T cells subsets including the memory subset. The dysbiosis also impacted the secretion of pro-inflammatory cytokines and overall hampered the successful clearance of M.tb in the murine model of TB (128).

A cohort study of western European population suggested the role of gut microbiome in altering BCG-induced specific and trained immune responses. The trained immune response against Staphylococcus aureus was negatively correlated with the abundance of Roseburia. Roseburia secreted metabolites affected the phenylalanine metabolism. The disturbed phenylalanine metabolism can dampen BCG-induced trained immunity. The abundance of Ruminococcus and Eggerthella lenta was correlated to be a positive indicator for M.tb control (129).

Actinobacterial abundance was correlated with positive T-cell response to BCG administration in a cohort study on Bangladeshi infants. The prevalence of Enterobacteriales, Pseudomonadales, and Clostridiales was demonstrated to be associated with neutrophilia and reduced vaccine efficacy (130).

Immunomodulatory molecules produced by microbiota such as flagellin, peptidoglycan, lipopolysaccharides, and SCFA acts as ligands to PRRs (Toll like receptors, NOD-2 receptors) and modulate innate and adaptive immune cells activation and metabolism. SCFA production has been linked to the generation of efficient B cell response through modulating B cell differentiation into antibody producing cells (131). Gut microbiome has also been shown to regulate antigen specific T cell responses. The microbiota has notable role in generation of type-1 interferon by plasmacytoid dendritic cells which can eventually signal conventional dendritic cells to prime T cell more efficiently (132). Microbial-encoded cross-reactive epitopes could also potentially modulate vaccine immune response (124). Administration of bacterial species in form of pro/prebiotics, or faecal transplant can be an important determinant towards optimizing microbiota composition. This optimization can prove to be beneficial therapeutic avenue to positively impact vaccine immunogenicity (133) Thus, understanding and harnessing the influence of the gut microbiome on vaccination responses could lead to more effective and targeted strategies for disease prevention.

In addition to the role as biomarkers, exosomes have the potential to be used for drug delivery systems due to their nano-lipid properties (155). Several in-vitro and in-vivo studies demonstrate the immune-activating properties of M.tb-infected innate immune cell-derived exosomes. M.tb antigen-loaded exosomes have demonstrated immune boosting properties which are critical in vaccine and adjuvant development for developing novel vaccine and immunomodulatory candidates (156, 157).

Exosomes carrying potent M.tb antigens hold a great promise to serve as a productive cell-free vaccine candidate to replace/boost BCG immunizations. Exosomes from M.tb-infected macrophages can direct the polarization of naïve macrophages. Additionally, exosomes derived from infected innate immune cells can effectively prime the adaptive T cells in the in-vivo model of TB (16). In yet another study on the murine model of TB, exosome vaccination has been found to prime as well as boost BCG immunization. Mice displayed a Th1-mediated immune response with limited Th2 response as compared to BCG-immunized mice. The purified exosomes used for vaccination showed notable enrichment with antigenic mycobacterial proteins (157).

EV derived from human neutrophils stimulated with M.tb results in a decrease in intracellular M.tb in the macrophages. The EVs derived from the in-vitro stimulated human neutrophils contains TLR ligands and co-stimulatory molecules required for innate and adaptive immune cell activation, respectively. The EVs induce autophagy to clear intracellular M.tb from the macrophages (158). Another research suggests the use of ubiquitin-tagged Ag85B-ESAT6 fusion protein-based exosome can be used as a novel vaccine candidate. This antigen-specific exosome-based delivery system has been observed to induce enhanced IFN-γ response by T cells and it enhances mycobacterial clearance (159).

Exosomes have also been tested as vaccine candidates for cancer in murine melanoma models. DC-derived exosomes were found to induce adaptive immune responses. The exosomes significantly augmented CD8⁺ T cell proliferation and differentiation into central memory cells (160). EVs have also been found to act as a superior adjuvant and elicit an effective cell-mediated immune response (161). In a study conducted on the murine model, exosomal adjuvant enhanced the IFN-γ secretion upon immunization with hepatitis B surface antigen. The role of exosomes as adjuvants during BCG immunization requires further research in TB (162). Exosomes function as a double-edged sword in the host-pathogen interaction. There are few studies suggesting exosomal contents can limit inflammation and delay mycobacterial clearance (16, 163).

Nevertheless, more research in the exciting field of exosomes is required to realize its full potential as a vaccine and adjuvant candidate to provide better protection against TB.