**1. Introduction**

Although the millennium development goal to stop tuberculosis (Tb) epidemic is almost achieved, still in 2012 there were 8.6 million new cases and 1.3 million deaths worldwide [of which 3, 20,000 people were co-infected with HIV too (WHO 2013)]. The rate of new Tb cases has been falling but decline rate at 2 percent per annum is still slow. Progress to handle multidrug resistant tuberculosis (MDR Tb)-defined by resistance to rifampicin and isoniazid (often accompanied by additional resistance), which accounts for 3.6 percent of the new and 20.2 percent of the previously treated Tb cases-is also slow (WHO 2013). Emergence of extremely drug resistant (XDR) strains of *Mycobacterium tuberculosis* (M tb) which is about 9.6 percent of the MDR Tb cases (WHO 2013) is a looming threat to the programmes aimed to stop tuberculosis. The XDR strains are resistant to isoniazid and rifampicin (first line drugs); at least to one of the three injectable second line drugs (amikasin, kanamycin or capreomycin) and also to any of the fluoroquinolone drugs to tuberculosis. The MDR and XDR Tb account for much higher death rates among the incident cases.

Induction of autophagy, Vitamin D and arachidonic acid metabolites play a decisive role in determining the susceptibility or resistance to the *Mycobacterium tuberculosis* infections. Additionally, cytokine responses play a major role. Among the cytokines, important ones are type I/ type II interferons, TNF-α and IL-1β in combination with other cytokines such as IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22 etc. (Ottenhoff TH, 2012). M tb has evolved strategies to suppress the immune response mounted against it and even exploits host molecular pathways for its survival benefits. Regulation of apoptosis versus necrosis by M tb or its host has emerged as a major player in determining the survival or clearance of the pathogen. Many of these pathways have components with opposite roles favouring either host or the pathogen. They

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

inflammatory response at the site of infection. Other cells of the innate and adaptive immune system migrate to the infection site and try to contain the bacterium by forming a specialized

Convergence of host immune mechanisms in *Mycobacterium tuberculosis* pathogenesis

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

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The granuloma plays a major role in preventing the escape of the bacterium to other sites and also creates a localized immune response. If the immune response directed against the pathogen is capable of successfully containing it, granulomas shrink with the formation of the caseous centres, which is the case in immune-competent individuals (Dannenberg AM Jr. and Rook JA, 1994; Doherty TM and Andersen P, 2005). M tb is unable to replicate within the caseous centres due to hypoxia, acidic pH and presence of the fatty acids which are toxic to the bacterium but some organisms become dormant and persist for many years (Smith I, 2003). However, if the bacterium is able to survive by utilizing various immune evasion tactics and is able to replicate, necrosis of the infected macrophages takes place. It leads to the degradation of cells composing the granuloma and lipids (especially cholesterol) from the dying cells serve as a rich source of nutrient for the bacterium (Orme IM, 2013). Subsequent destruction of the cells leads to liquefaction within the interior of the granuloma where bacteria lives an apparently extracellular life, probably in the form of a pellicle or biofilms (Ojha AK et al., 2008; Orme IM, 2013) – a part of the bacterial life cycle not well perceived in the scientific arena. At this stage, the pathogen is far from the reach of current drugs available for treating tuberculosis and the components of the immune system modulated by the vaccine to tackle the infection (Orme IM, 2013). The calcification process initiated inside the granuloma after necrosis push the bacterium to the periphery and probable rupture of the membrane leads to dissemination of the bacterium. At this point, M tb is capable of dissemination to other organs of the body and is also released to the external environment as aerosol droplets when the host

coughs, sneezes, shouts or sings and thus is able to start a new cycle of infection.

the recent research in the area has been highlighted.

**2. Interferon signalling**

Though a high number of people fall prey to the bacterium very often but remain asympto‐ matic unless there are perturbations in the immune status of the person. The probability of developing active disease after getting infected is high in the initial two years but at least 5-10 percent of the people develop disease during their lifetime (Harada N, 2006; O'Garra A et al., 2013). In this chapter some of the host molecular pathways or their components and the signalling axes which play crucial roles in the inhibition or survival of the M tb and some of

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

structure called granuloma.

#### **1.1. Tb epidemiology**

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.

#### **1.2. M tb pathogenesis**

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 inflammatory response at the site of infection. Other cells of the innate and adaptive immune system migrate to the infection site and try to contain the bacterium by forming a specialized structure called granuloma.

The granuloma plays a major role in preventing the escape of the bacterium to other sites and also creates a localized immune response. If the immune response directed against the pathogen is capable of successfully containing it, granulomas shrink with the formation of the caseous centres, which is the case in immune-competent individuals (Dannenberg AM Jr. and Rook JA, 1994; Doherty TM and Andersen P, 2005). M tb is unable to replicate within the caseous centres due to hypoxia, acidic pH and presence of the fatty acids which are toxic to the bacterium but some organisms become dormant and persist for many years (Smith I, 2003). However, if the bacterium is able to survive by utilizing various immune evasion tactics and is able to replicate, necrosis of the infected macrophages takes place. It leads to the degradation of cells composing the granuloma and lipids (especially cholesterol) from the dying cells serve as a rich source of nutrient for the bacterium (Orme IM, 2013). Subsequent destruction of the cells leads to liquefaction within the interior of the granuloma where bacteria lives an apparently extracellular life, probably in the form of a pellicle or biofilms (Ojha AK et al., 2008; Orme IM, 2013) – a part of the bacterial life cycle not well perceived in the scientific arena. At this stage, the pathogen is far from the reach of current drugs available for treating tuberculosis and the components of the immune system modulated by the vaccine to tackle the infection (Orme IM, 2013). The calcification process initiated inside the granuloma after necrosis push the bacterium to the periphery and probable rupture of the membrane leads to dissemination of the bacterium. At this point, M tb is capable of dissemination to other organs of the body and is also released to the external environment as aerosol droplets when the host coughs, sneezes, shouts or sings and thus is able to start a new cycle of infection.

Though a high number of people fall prey to the bacterium very often but remain asympto‐ matic unless there are perturbations in the immune status of the person. The probability of developing active disease after getting infected is high in the initial two years but at least 5-10 percent of the people develop disease during their lifetime (Harada N, 2006; O'Garra A et al., 2013). In this chapter some of the host molecular pathways or their components and the signalling axes which play crucial roles in the inhibition or survival of the M tb and some of the recent research in the area has been highlighted.
