Exposure to M.tb occurs when an active TB patient releases the infectious droplets in the air during coughing, sneezing, or talking. The bacteria in the droplet nuclei are infective to another person when inhaled.

The M.tb in the droplet nuclei when inhaled by another individual is carried to the alveoli where they infect macrophages and multiply inside them. Within 2–6 weeks, the infection is followed by cellular immune response generated by CD4+ T-lymphocytes and infected macrophages release cytokines and chemokines. In 70–90% of instances, the immune response of an individual is strong enough, and it will fight off the TB bacteria and not become infected.

During M.tb infection, the host immune response is able to contain the mycobacterial infection at the site of infection in approximately 30% of cases, but is unable to “sterilize” them. These foci later become associated with a state of LTBI with M.tb where persons are healthy, asymptomatic, and the infection is present in an enclosed environment in a non-transmissible state. The cellular immune response leads to the formation of a granuloma and the infection is curtailed. It also generates a delayed-type hypersensitivity reaction. Globally in 2014, approximately 1.7 billion individuals were estimated to be latently infected with M.tb and form a reservoir for future TB disease (2).

This can occur with weakening of immune responses. If person is unable to control the initial infection, it can progress to active primary disease as in children. If the infection is curtailed and goes into latency, with the weakening of the immune system, it can progress to disease even months or years later; by breakdown of granuloma and active uncontrolled replication of mycobacteria with resultant disease in lungs and other organs (3).

The likelihood of getting infected with M.tb as well as the subsequent development of active disease depends upon number of factors like the infectivity of the source case, proximity and duration of contact, susceptibility of the host and various social, behavioral, economic, and environmental factors like undernutrition, overcrowding, indoor air pollution, smoking, and alcohol addiction (4–7). Of these, undernutrition is the single most important predisposing factor for TB in many resource limited settings (8).

Malnutrition is known to have direct effects on T cells. Severe PEM provokes atrophy of thymus as well as peripheral lymphoid organs, which in turn reduces cell number (leukopenia), decreases CD4/CD8 ratio, increases numbers of CD4 and CD8 double-negative T cells, and increases the number of immature T cells in the peripheral blood (14). A major decrease in the expression of CD25 and CD27 (the molecules required for T cell activation and proliferation) was also demonstrated. Immune response of the gut mucosa is also affected by malnutrition. It results in flattened hypotrophic microvilli, reduced IgA secretion, and lymphocyte counts in Peyer’s patches (15). Malnourished children have shown reduced production of type 1 cytokines (IL-2 and IFN-γ), which are the main mediators of immunity (16). Such changes in cell-mediated immunity lead to increased susceptibility of an individual to infection. Similarly, low serum albumin levels (<2.7 g/dl) has been shown to be strongly and independently associated with in-hospital deaths due to TB (aOR 3.38, 95% CI 1.51–7.59; P = 0.001) (17).

There are two classes of essential fatty acids [n6 and n3 polyunsaturated fatty acids (n6 and n3PUFA)], which share the common enzyme system for their metabolism and their metabolic end products are mostly distinct in action. There are contrasting evidences to support the effects of these fatty acids in M.tb survival and proliferation (18). One of the important mechanisms by which the M.tb survives in the macrophages is by inhibiting the membrane actin assembly, which is essential for the maturation of phagosomes. The in vitro studies on effect of lipids on M.tb survival in macrophages showed that adding eicosapentaenoic acid (n3 PUFA) to culture medium favor M.tb growth. The suggested mechanism for this is inhibition of actin filament assembly while arachidonic acid (n6 PUFA) promotes it (19). The same group tested the in vitro results in an animal model and found a contrasting observation that n3 PUFA promoted M.tb clearance while n6PUFA helped M.tb survival suggesting the presence of complex metabolic and immunologic interplay (20). The enrichment of anti-inflammatory n3PUFA in host cells is also beneficial for T-cell mediated immune reactions but detrimental to macrophage-mediated microbial clearance (21). The M.tb survival in the host depends on the regulation of “Eicosanoids”—the complex metabolic end products of n6PUFA. The virulent M.tb diverts the metabolic pathway toward the production of lipoxin A4 and thereby inhibits cyclooxygenase 2 and decreases the levels of prostaglandin E2 (PGE2), which is a metabolic end product of arachidonic acid. By limiting the PGE2, which is involved in cellular repair, M.tb produces a necrotic environment in macrophages and thereby proliferates further.

Sphingolipids are structural lipids, which include sphingomyelin, ceramide, and sphingosine 1-phosphate, which are abundant in neuronal tissue and considered important bioactive molecule of inflammation. Sphingosine-1-phosphate, with effects over calcium regulation, expression of growth factors and inflammatory cytokines are of major interest in the regulation of M.tb survival (22). There are several mechanisms proposed for the survival and proliferation of M.tb in the host cell by which the M.tb evades the defense mechanism of the host. One of them involves direct action over the bioactive lipids and thereby altering the calcium influx in to the cytosol. Upon binding of microbes with the surface membrane receptors of the macrophage, an enzyme called sphingosine kinase 1 (SPK1) gets activated. The activated SPK1 phosphorylates the sphingosine to sphingosine 1 P (S1P) and the bioactive S1P initiates a cascade of events to release the Ca²⁺ in the cytosol, which is essential for the maturation of the phagolysosome. The M.tb cell wall glycolipid lipoarabinomannan (LAM) dephosphorylates the SPK1 by stimulating the Src homology region 2 domain-containing phosphatase1 (SHP1) in host monocytes and prevents the translocation of SPK1 to the membrane and thereby prevents the maturation of the phagosome. The inhibitory activity of LAM over SPK1 is also very effective in decreasing the inflammatory molecules such as TNF-α, IL-12, etc., of the host (23). The immunomodulatory actions of M.tb such as intracellular release of LAM help M.tb to evade the adaptive immune clearance by suppression of the maturation of phagolysosome.

Many studies have reported vitamins as a key mediator of innate immune system by regulating the functions of both macrophages and DCs and immunomodulating the process of antibacterial functions, autophagosomes formation, autophagy, and cytokine production. Multiple vitamins have been shown to have a role in immunity against M.tb infection or disease (24–28).

Vitamin D has been recognized as a vital modulator of both innate and adaptive immune response against TB infection, enhancing the antimicrobial properties of the phagocytes viz., monocytes, macrophages, DCs, and neutrophils.

Essentially, 1, 25-dihydroxyvitamin D3 induces the differentiation of monocytes into macrophages at the site of infection and enhance the uptake of the bacterium by promoting phagocytosis (29, 30); upregulate specific markers like CD14, mannose receptor, DC sign over the surface of antigen-presenting cells to boost the phagocytic activity, and intracellular killing (30). Besides, Vitamin D also induces the expression of several antimicrobial peptides, particularly cathelicidin (CAMP) and β-defensin 2(DEFB4). Vitamin D also induces hCAP18, which triggers the autophagy mechanism of the infected cells, by mediating phagosome–lysosome fusion and plays a vital role in the elimination of the intracellular M.tb (31). In addition, vitamin D is found to downregulate the expression of HAMP (hepcidin antibacterial protein), which aids in the intracellular transport of iron, thereby suppressing the growth of the bacteria within macrophages (32).

Besides macrophages, DCs (especially the myeloid DCs) also get modulated during the antigen presentation process, by Vitamin D, during mycobacterial infection. Vitamin D suppresses DC differentiation and maturation by downregulating NF-Kb through transcription control of relb gene (33). Vitamin D also modulates T helper cells by downregulating the production of proinflammatory cytokines such as interferon-gamma (IFN-γ), interleukin (IL-6, IL-12), tumor necrosis factor (TNF-α), and other related chemokines and escalating the production of the anti-inflammatory cytokines like TGF-β, IL-4, and IL-10 (34, 35). Vitamin D also modulates the proinflammatory response by downregulating the TH1 and TH17 response and regulates the excessive inflammatory response during active mycobacterial infection. Nevertheless, vitamin D has suppressive role against proliferation of activated B cells, generation of plasma cells, and class switched memory cells, thereby reducing the levels of secreted immunoglobulin, which indirectly contributes to the downregulation of proinflammatory response and in turn promotes anti-inflammatory response by stimulating B-regs (36, 37). Vitamin D also modulates the inflammatory process by attenuating the expression of M.tb induced matrix metalloproteinase (MMPs) such as MMP-7, MMP-9, and MMP-10. With the help of CYP27B1 and Vitamin D receptors, Vitamin D3 induces cathelicidin gene encoded antimicrobial peptide LL37, which in turn increases the intracellular calcium levels and results in direct killing of M.tb. Increased levels of LL37 results in augmented differentiation of macrophages, bacterial killing through increased intracellular Ca2+ levels, and decreased M.tb-induced MMP 7, 9, and 10 and vitamin D-mediated TLR2 and 4 expression together with upregulation of IL-10. All these roles of Vitamin D have a definite impact on the progression and outcome of TB disease in an individual. Two meta-analyses have demonstrated that low serum vitamin D levels are associated with susceptibility to M.tb infection as well as progression to TB disease rather than low vitamin D levels being a consequence of the disease (38, 39). A study from South Africa has also identified that polymorphisms in gene associated with innate immunity, in combination with low vitamin D levels increase a child’s risk of developing TB disease or death (40).

Supplementation with vitamin D along with anti-TB treatment may be beneficial with respect to minimizing the excessive tissue damage that occurs during the active stage of TB disease. Several clinical trials have evaluated vitamin D supplementation as an adjunct therapy in the treatment for TB (41–44). However, results are conflicting, owing to variations in dose regimens and outcomes. Further investigations are needed to find the optimal concentration of vitamin D for supplementation with standard anti-TB drugs to optimize treatment, which could help to effectively manage both drug-sensitive and drug-resistant TB.

Essentially, metals like iron, manganese, copper, and zinc are very much needed for the survival of M.tb inside the macrophages. M.tb has accomplished features to acquire these metals from the cellular milieu and utilize them for survival and replication within the macrophages. Host immune system tackles the mycobacterial infection by sequestering metals like copper and zinc in the phagosomes beyond their normal levels and tries to kill them by metal poisoning. Alternatively, by means of nutritional immunity and with the help of translocation of metal transporter proteins, essential metals like iron and manganese will be depleted within the macrophages and thus prevent the replication of the bacilli (45, 46). In addition, iron homeostasis also differs between early and delayed TB-progressors, with higher ferritin and hepcidin concentrations observed among early TB-progressors among household contacts (47). It has been shown that both iron deficiency and overload exists in TB patients that affect the disease progression and clinical outcomes (48). Besides iron, manganese will also be depleted from the phagolysosomes through NRAMP1 with coordinated response of transferrin, ferritin, and hepcidin. Thus, the negative regulatory effect of iron and IFN-γ increases the antimicrobial function through increased production of IL-4/IL-10/IL-5/FOXP3, which results in decreased DCs maturation, function, and differentiation. In addition, pathways related to the production of Nos2 and TNFα mediate killing of M.tb. Innate immune response against M.tb can be strengthened by pumping of copper and zinc ions inside the phagolysosomes for bactericidal activity.

In natural conditions, upon ingestion of immunogenic foreign bodies, the macrophages get stimulated and their intracellular Ca²⁺ ion concentration increases 10-fold than that of their non-stimulated state. The Ca²⁺ ions are very essential for several events associated with phagocytosis including activation of the Ca2+/CAM-dependent protein kinase II (CAMKII) and generation of reactive oxygen molecules. Selective inhibition of formation of Ca2+ CAM complex formation (pre translocation) or inhibition of CAMKII pathway on the surface of the phagosome (post-translocation) prevent the maturation of the phagosome (49). It is also been established that the effect of Ca2+/CAM/CAMKII complex on phagosome maturation is associated with series of events that are specifically involved in the phagosome–lysosome fusion (50). Table 1 gives an overview on the effect of macro and micro nutrient on immunomodulation that are discussed and referenced in this review.

In brief, Figure 1 represents a schematic diagram of the role of all nutrients explained above during M.tb infection. Upon infection, a series of antimicrobial effector mechanisms will be triggered by macrophages. M.tb also inhibits cycoloxygenase2 (cox2) pathway and limits prostaglandin 2 (PGE2), which is shown to be involved in membrane repair and apoptosis. By limiting PGE2, M.tb diverts the apoptotic pathway toward necrosis, which is essential for M.tb survival and proliferation.