**2. Interferon signalling**

also are interconnected and the final outcome of the infection depends on the result of their

Tb incidence is generally considered as notifications of the cases with correction for underre‐ porting and non-diagnosis. The total incidence of Tb cases in 2012 was in the range of 8.3-9.0 million globally (WHO 2013). Out of these, children account for 0.5 million cases and 3.1 million cases were among women. According to the WHO report on tuberculosis, most of the cases were from Asia and African regions-India (2.0-2.4 million), China (0.9-1.1 million), South Africa (0.4-0.6 million), Indonesia and Pakistan with 0.45 million and 0.4 million cases respectively, which is dangerously high. The report suggests that it is developing countries and specifically, the poor who are gripped tightly by the disease and who account for the maximum number of new cases and deaths worldwide. Awareness and access to diagnostic labs in developing countries is still low in addition to the lack of availability of affordable treatment. The combi‐ nation of factors results in the spread of the pathogen to many people before being diagnosed. Diagnostic methods to distinguish latent tuberculosis from active disease and treatment options for latent Tb also are urgently required otherwise tuberculosis cannot be eradicated completely. There is some progress in this area and newer methods to diagnose latent Tb are being developed (Singh SB et al., 2013). In a recent study, Harari A et al. 2011, showed the possibility of discriminating latent Tb from active disease which could not be differentiated by a tuberculin skin test (TST) or interferon gamma release assay (IGRA). They utilized a flowcytometry based method and analysed the functionality of M tb specific CD4 T cells from cohorts. Their results suggests that CD4 T cells are multifunctional and able to produce IL-2, TNF-α and IFN-γ in latent Tb cases while they dominantly produce TNF-α (single positive) in active disease conditions (Harari A. et al. 2011). Also since BCG is almost 100 years old with varied efficacy, new pre-and post-exposure vaccines are needed to prevent tuberculosis.

The genus Mycobacterium originated millions of years ago, but the members of the M tb complex evolved about 15,000-35,000 years back (Gutierrez MC et al., 2005). The noted occurrence of tuberculosis in humans is from their prehistoric remains and from Egyptian mummies dated back to 3000-2400 years (Zink AR et al., 2003). Respiratory tract is the main route of entry of the pathogen as airborne droplets containing the bacterium reaches the lunga suitable site for this aerobic organism to establish infection. However other tissues and organs viz. lymphatic system, central nervous system, pleura, liver, spleen, bones and joints are also susceptible to infection by M tb and manifestation of the disease (Bloom BR and Small PM, 1998; Golden MP and Vikram HR, 2005). Once in the lung, alveolar macrophages engulf the bacterium, a process facilitated by binding of the lipo-arabinomannan on the bacterial cell wall to the mannose receptors on macrophages. Complement receptors on the macrophage surface also take part in the process of endocytosis of opsonised M tb (Ernst JD, 1998; Kang PB et al., 2005; Kerrigan AM and Brown GD, 2009). These interactions culminate in the release of cytokines which stimulate the adaptive arm of the immune system and eventually leads to

converging effects.

74 Trends in Infectious Diseases

**1.1. Tb epidemiology**

**1.2. M tb pathogenesis**

Type I interferons e.g. interferon-α and interferon-β are implicated in progression of the tuberculosis. Mice with impaired type I interferon signalling are better protected from the pathogen (Manca C et al., 2001). *In-vitro* studies also show that M tb infection leads to up regulation of the genes of type I interferon signalling pathways and genes induced by them (Remoli ME et al., 2002). On the other hand interferon-γ, a type II interferon is critically important in protection against tuberculosis (Flynn JL et al., 1993; Trinchiari G, 2010). It plays its role by various mechanisms including activation of macrophages, enhances functioning of 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 could be novel targets for Tb treatment.

(PRR) TLR2/TLR6 and NOD2 (Kleinnijenhuis J et al., 2009). TLR4, the other PRR which is important in M tb recognition does not play major role in production of IL-1β. The immune adaptor molecule MyD88 has a central role in the transcription of the IL-1β mRNA during M

Convergence of host immune mechanisms in *Mycobacterium tuberculosis* pathogenesis

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

77

Absence in melanoma 2 (AIM2) inflammasome is a cytosolic sensor of the DNA and recognises DNA viruses and intracellular bacteria. Co-localisation of M tb DNA with AIM2 inflamma‐ some has been observed suggesting their direct interaction (Saiga H et al., 2012). AIM2 inflammasomes are involved in activation of macrophages and secretion of IL-1β during infection with pathogenic strain of *Mycobacterium bovis* suggesting its co-operative role in host immunity (Yang Y, 2013). AIM2 deficient mice are more susceptible to M tb infection and are defective in production of IL-1β and IL-18 and mount poor Th1 response (Saiga H et al., 2012). These authors also speculated on the role of AIM2 inflammasome in suppressing type I interferons in M tb infections. NLRP3 inflammasome is implicated in the protective immune response to M tb infection by facilitating the maturation process of IL-1β (Rathinam VA et al., 2012). However, M tb suppresses the activation of the NLRP3 inflammasome by inducing IFNβ, while IFN-β induces the AIM2 inflammasome which is detrimental to the pathogen (Fernandes-Alnemri T et al., 2010; Tsuchiya K et al. 2010; Briken V et al., 2013). Thus M tb balances the level of IFN-β such that NLRP3 inflammasome is kept suppressed and the AIM2 inflammasome is not allowed to be activated. This is done by the ESX-1 secretion system which is dependent on the ESAT6-an RD1 region encoded protein of M tb (Shah S et al., 2013).

Activating inflammasomes, although critical for protection from M tb infection and tubercu‐ losis, also need to be regulated to prevent the tissue damage and rampant inflammation. Host regulation of NLRP3 inflammasome is done by nitric oxide which acts as its negative regulator during M tb infection and consequently controls the level of IL-1β (Mishra BB. et al., 2013).

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

tb infection (Kleinnijenhuis J et al., 2009).

**5. Arachidonic acid metabolites**
