**5. Arachidonic acid metabolites**

CD8 T cells and through reactive nitrogen species (Flynn JL et al., 1993; Green AM et al., 2013). Thus both types of interferons have important and opposite roles in determining the mycobacterial pathogenesis (Teles RM et al., 2013). Berry et al., 2010, found a Tb-specific transcriptional signature in blood which could help in discrimination between latent and active disease and also distinguishes Tb from other infectious and inflammatory diseases. They reported 86 gene signatures which are specific to tuberculosis. These genes are mostly interferon inducible and consists of both type I and type II interferon signalling pathways and

IL-1β imparts immunity to tuberculosis and mice lacking in IL-1β or its receptors are suscep‐ tible to M tb infection (Mayer-Barber KD, 2010). It is an important factor in host immunity and virulent mycobacteria suppress the IL-1β production which is regulated by type I interferons in macrophages (Novikov A et al., 2011). IL-1β has been shown to possess bactericidal activity in the macrophages derived from murine and humans (Jayaraman P et al., 2013). It upregulates secretion of tumor necrosis factor (TNF) and cell surface expression of TNFR1, thus facilitates TNF signalling which culminates in caspase-3 activation leading to growth inhibition of M tb through apoptosis of the infected macrophage (Jayaraman P et al., 2013). They also showed that this effect of TNF on the M tb infected macrophage is due to autocrine mode of action. In synergy with vitamin D, IL-1β drives transcriptional expression of the antimicrobial peptide genes such as defensin beta 4 (DEFB4), cathepsins, cathelicidins and ubiquitin derived peptides which have M tb killing ability (Alonso S, 2007; Liu PT et al, 2009; Ottenhoff TH, 2012). Results from the work of Liu PT et al. 2009, also suggest that the coherent action of IL-1β and vitamin

IL-1β being a pro-inflammatory cytokine is under tight regulation to prevent the immunepathology and subsequent tissue damage during chronic infections. Mishra et al., 2013, showed that level of this cytokine is regulated by IFN-γ induced release of nitric oxide (NO) which in turn regulate the inflammasome NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3) during M tb infections. This regulation happens at the stage of caspase1 mediated processing of pro-IL-1β to IL-1β and is specifically NLRP3

As briefly discussed above inflammasomes play a regulatory role in tuberculosis and imparts protection if activated. For its survival M tb prevents the activation of inflammasomes, caspase-1 dependent processing of pro-IL-1β and phagosome maturation through its gene zmp1 (Master SS et al., 2008; Lazarevic V and Martinon F, 2008). It has been shown that the production of IL-1β is dependent on the recognition of M tb by pattern recognition receptors

D is an integral part of the TLR2/1 signalling mediated antimicrobial activity.

could be novel targets for Tb treatment.

76 Trends in Infectious Diseases

dependent (Mishra BB. et al., 2013).

**4. Inflammasomes in tuberculosis**

**3. IL-1β signalling pathway in tuberculosis**

M tb on engulfment by macrophages tries to prevent the apoptosis of the harbouring macro‐ phage so that it can establish a niche for itself. It also promotes necrosis of the macrophages in which it resides which help its spread to the neighbouring cells before establishment of the adaptive immune response of the host (Divangahi M et al., 2013). Several lines of research suggest that metabolic products of arachidonic acids such as leukotrienes, lipoxins and eicosanoids play decisive roles by regulating innate and adaptive immunity in the mycobac‐ terial pathogenesis (Divangahi M et al., 2010). The prostaglandins and lipoxins, metabolites of arachidonic acid, have opposite roles. While prostaglandins such as prostaglandin E2 (PGE2) is pro-inflammatory in nature and promotes apoptosis, lipoxins inhibit it and promotes necrosis which results in the spreading of the bacterium (Tobin DM et al., 2010). Lipoxins e.g. Lipoxin A4 and its metabolites are anti-inflammatory in nature, repress TNF-α and stops neutrophil recruitment to the site of infection (Tobin DM et al., 2010). The other metabolite leukotriene B4 (LTB4) enhances level of TNF-α and thus creating a state of hyper-inflammation which is also not a healthy state for the host. Thus, TNF-α is regulated by metabolic products of arachidonic acid to keep its optimum level so that M tb infection is controlled while hyperinflammation is also prevented.

It is shown that pathogenic mycobacteria synthesize oxygenated mycolic acids which induce foamy cell formation of the macrophages (Peyron P et al., 2008) but this might not hold true under hypoxic conditions (Daniel J et al., 2011). Peyron P et al., 2008 have shown that these lipid droplets serve as nutritional source to the pathogen and help in its non-replicative life cycle and persistence. One recent report also suggested that mycobacterium prevents lipolysis by interfering with the host lipid metabolic pathways, which leads to lipid accumulation inside the macrophage (Singh V et al., 2012). These lipids serve as a source of nutrition and help the pathogen in its dormant lifestyle. The specific presence of foamy macrophages in the necrotic regions has been suggested that they play crucial role in necrosis and hence in spreading of the bacterium (Peyron P et al., 2008). Although macrophages are the frontline innate immune cells, it is clear that their foamy phenotype helps the pathogen in establishing persistent infection and the host innate and adaptive immune response is no more able to eliminate the pathogen once it happens. Thus the ideal way to target the pathogen is before the establishment

Convergence of host immune mechanisms in *Mycobacterium tuberculosis* pathogenesis

http://dx.doi.org/10.5772/58319

79

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

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,

M tb, besides evading host immune response against it also delays the onset of the adaptive immunity (Urdahl KB et al., 2011). M tb engulfed by macrophages tries not only to prevent apoptosis of harbouring macrophage but also promotes its necrosis which helps in spread of

in inflammation and related phenomenon (Castillo EF, 2012; Deretic V, 2012).

of the foamy phenotype of the macrophages harbouring the M Tb.

**8. Role of autophagy**

2005; Yuk JM et al., 2009).

**9. Conclusions and future perspectives**
