**8. Role of autophagy**

of arachidonic acid to keep its optimum level so that M tb infection is controlled while hyper-

Deficiency of vitamin D is associated with higher incidence and manifestation of tuberculosis (Nnoaham KE, 2008; Verway M et al., 2013) and its supplementation helps to overcome this disease. Vitamin D is also able to restore the impaired secretion of TNF-α from macrophages of HIV-positive people (Anandaiah A et al., 2013). It acts as a mediator of innate immune response against M tb by mediating signals from toll like receptors to the activation of antimicrobial peptides (Liu PT et al., 2006). Liu PT et al. 2006, demonstrated that TLR stimu‐ lation by M tb or lipo-polysaccharide activates vitamin D receptors and subsequent down‐ stream signalling activates transcription and translation of cathelicidin, a peptide with antimicrobial properties and thus creating an antimicrobial state in the human macrophages. Vitamin D has a modulatory role on the levels of cytokines specifically IL-1β and thus aid in immunity to the pathogen (Verway M et al., 2013). It also regulates the role of NLRP3/ caspase1 inflammasome leading to regulation of the levels of IL-1β and cross talk between alveolar epithelial cells and macrophages which is required for the synthesis and release of anti-

1, 25-dihydroxyvitamin D3, the active component of vitamin D, plays a major role in induction of autophagy during M tb infections (Yuk JM et al., 2009). This function of vitamin D3 is performed by activation of transcription of Beclin-1 and Atg5 genes and is mediated by cathelicidins (Yuk JM et al., 2009). Vitamin D3 also helps in the formation of autophagosomes, autophagolysosomes and co-localization of M tb cells with them, an important step in the

After being engulfed by macrophages M tb dys-regulates its lipid metabolism which leads to lipid accumulation within a subset of these macrophages giving them a characteristic foamy phenotype. The lipid packed foamy macrophages have been associated with several chronic disease conditions such as atherosclerosis and during infections with persistent intracellular pathogens e.g. M Tb, Chlamydia and Toxoplasma (Kalayoglu MV and Byrne GI, 1998; Portugal LR et al., 2008; Galkina E and Ley K, 2009). Triglycerides, phospholipids and cholesterol constitute the low density lipo-proteins (LDL) and in foamy macrophages the influx and efflux of LDLs is dys-regulated (Russell DG, et al., 2009). Cholesterol gets esterified when the macrophage attains foamy phenotype and is retained as lipid droplets (Russell DG et al., 2009). Recently it has been shown that triacylglycerols (TAG) of M Tb are derived from host TAG and are imported by the bacterium for its lipid synthesis (Daniel J et al., 2011). M tb incorporates host derived lipids directly into its own pool and the accumulation of neutral

inflammation is also prevented.

microbial peptides (Verway M et al., 2013).

killing of the bacterium (Yuk JM et al., 2009).

lipids by the M tb leads to its lipid fastness (Daniel J et al., 2011).

**7. Role of foamy macrophages**

**6. Role of vitamin D**

78 Trends in Infectious Diseases

In addition to the above discussed mechanisms, hosts also try to clear the pathogen by inducing autophagy-an innate defence against M tb (Kumar D et al., 2010; Jo EK, 2013). Nutrient starvation, stress and activation of the specific cytosolic receptors induce autophagy (Ottenhoff TH, 2012). By this process protein aggregates, damaged organelles and cytosolic pathogens are sequestered inside the autophagosomes. The subsequent fusion of the auophagosome with lysosomes leads to degradation of the trapped entities and this process is prominently involved in the clearance of intracellular pathogens including mycobacteria (Gutierrez MG et al., 2004; Alonso S, 2007; Levine B et al. 2011; Cadwell K and Philips JA, 2013). This process is carried out by the product of autophagy related gene (Atg), Beclin 1 in combination with kinase genes PIP3-VPS34 and the GTPase-IGRM (Deretic V. 2010). The role of autophagy is also suggested in inflammation and related phenomenon (Castillo EF, 2012; Deretic V, 2012).

Autophagy regulates innate and adaptive immune pathways viz. antigen presentation to T cells by macrophages and dendritic cells (Jagannath C, 2009; Ottenhoff TH, 2012) and inflam‐ matory responses (Levine B et al. 2011). Thus autophagy plays an effector function during M tb pathogenesis, however this process itself is regulated by vitamin D. Vitamin D up regulates autophagy and plays bridging role between innate and adaptive immune arms (Deretic V, 2005; Yuk JM et al., 2009).
