**2. The encounter of Mtb with the innate immune system**

Most human infections with MTB occur through inhaled carrier droplets into the lower airways. There the microbe encounters the alveolar macrophage (AMac) and submucosal

dendritic cell (DC). The outcome of the ensuing battle will determine whether the infection will remain locally limited within the engulfing cells of the innate immune system, or will continue to spread, causing the individual to become a clinically active TB patient [1,6,7,8]. During the first contact, the AMac recognizes the microbe through pattern recognition receptors (PRRs), which sense microbial biochemical components, such as outer coat manno‐ sylated lipoarabinomannan (ManLam), trehalose dimycolate and N-glycolymuramyl dipep‐ tide. These molecules act as pathogen-associated molecular patterns (PAMPs), which trigger an intracellular signaling cascade in the AMac, which leads to a phagocytic activity, which, if successful, will result into the complete engulfing of the microbe into cytosolic vesicles- the phagolysozomes and secretion of pro-inflammatory cytokines, such as tumor-necrosis factor alpha (TNFα). ManLam also binds directly to mannose receptors on macrophages and DCs.

This contrasts with the function of the phagosomal metal transporter natural resistanceassociated membrane protein (NRAMP) 1 to deprive the microorganisms from essential nutrients, such as iron and manganese [20]. Such duality existing in the same cell is of interest. Virulent Mtbs have acquired the capability to dampen the activity of NF-Kb by some of their antigens [6,7], such as ESAT-6 and ManLam. The latter also inhibits the secretion of IL-12, an essential cytokine in the anti-MTB inflammatory response. ESAT-6 downregulates MyD88- IRAK 4 interaction, thereby also interfering with TLR signaling to NFkB. A third antigen-CFP-10 markedly reduces nitric oxide (NO) and reactive-oxygen species (ROS) production by the macrophages, thereby inhibiting their non-specific killing ability. The microbe may also regulate macrophage apoptosis to its advantage and to inhibit IFNγ- mediated macrophage activation [7]. ESX is a recently discovered protein transport system through the outer membrane of the microbe, which is essential for its survival. It has been demonstrated, in an experimental model, that ESX-5 may modulate macrophage reactivity by dampening the inflammasome activation [21]. These mechanisms enable the microbe to survive in the macrophage phagosome in a balance which is precarious to the host. In addition Mtb may escape the phagolysozome into the cytosol by damaging its membrane. Most recently it has been described that the microbe may secrete toxins, such as the newly discovered MtpA protein, through its outer membrane into the macrophage cytosol, which may cause the death

The Immune Response to *Mycobacterium tuberculosis* Infection in Humans

http://dx.doi.org/10.5772/54986

21

Vitamin D seems also to play an important role in the microbe-host pull-of-arms [23]. It may modulate the inflammatory effect of some metalloproteinases (MMPs) in the lung [24] and Vitamin D supplementation has hastened bacterial eradication in pulmonary tuberculosis in

Thus, the encounter between MTB and the various components of the innate immune system induce a complicated and sophisticated series of host responses and counter responses by the microbe. The later is one of the most ancient human infections, carried by our ancestors since they fanned-out from Africa across the globe, therefore enabling it to adapt to the human

However, the next long-term phase of the encounter is played by the activation of the adaptive

In the previous section the importance of the host innate immune response in the encounter with MTB was described. However, it is generally accepted that the long-term outcome of the primary infection is determined by the effective mobilization of the adaptive immune re‐ sponse. Active TB patients, as well as latently infected carriers, do not suffer from a general innate or adaptive immune defect. On the contrary, ex-vivo studies of their immunocyte function demonstrate increased lymphocyte proliferation and the secretion of numerous cytokines [27]. Thus the disease, in people generally healthy, is a result of a very specific

immune response (26-Cole S, Tuberculosis in time and space, Econference).

**3. The role of adaptive immunity in the outcome of the Infection**

immune system, as described in the next section.

immune failure in face of MTB, or other mycobacteria.

of the later by cell necrosis [22].

a clinical trial [25].

The best studied PRRs are Toll-like receptors (TLRs) [6,9,10], of which 10 have been identified in humans. TLR- 2 and TLR-4 recognize bacterial products [9,11], TLR-2 having a major role in recognizing MTB in the lung. All contain an intracellular TIR domain, the activation of which initiates a signaling cascade via adapter proteins such as MyD88, interferon-inducing TRIF and TRIF-related adapter molecule TRAM, which results in the recruitment of interleu‐ kin-1(IL-1) receptor-associated kinase (IRAK) 4, which phosphorylates IRAK-1. The latter binds to TNFα receptor-associated factor (TRAF) 6, leading to kinase-dependent IkBα phosphorylation, the degradation of which leads to the activation of nuclear NF-kB, which is the main nuclear activator of proinflammatory cytokines. Another intracellular PRR is nucleotide-binding oligomerization domain 2 (NOD2), which binds bacterial cell-wall muramyl-dipeptide, eliciting secretion of TNFα, IL-1β, IL-6 and bacteridal LL-37 [12,13]

Neutrophils also play a defensive role, not only as first-line non-specific phagocytes, but also by secreting anti-bacterial proteins, mainly the cathelicidin LL-37 [1,14]. Neutrophils loaded by phagocytized bacteria become apoptotic, thereby eliciting macrophage activation [15].

NK cells, which are large granular circulating lymphocytes, are attracted to the sites of bacterial infections, where they specialize in recognizing and destroying infected host cells. During this process they secrete interferon gamma (IFNγ), which activates macrophages, inducing them to secrete the cytokines IL-12, IL-15 and IL-18, which activate CD8+T-cells, thus forming the link to the adaptive immune system [7,16]

The complement is the humoral arm of the innate immune system. It has been shown that M. bovis BCG may activate the three pathways of complement: the classical pathway by binding to the C1q protein, the lectin pathway by binding to the bacterial cell surface mannose-binding lectin (MBL) or L-ficolin and the alternate pathway through the deposition of C3b on the bacterial surface. Mtb can activate the classical and alternate pathways by binding C3. This enables complement to perform its major functions-microbial opsonization, microbial cell lysis through the formation of the attack complex and leukocyte recruitment by eliciting chemokine secretion [7,17].

Another recently discovered anti-microbial mechanism of phagocytic cells is the use of vital transition metals, such as iron, zinc and copper, to poison intracellular microorganisms. However, mycobacteria have developed a resistance mechanism to such intoxication [18,19]. This contrasts with the function of the phagosomal metal transporter natural resistanceassociated membrane protein (NRAMP) 1 to deprive the microorganisms from essential nutrients, such as iron and manganese [20]. Such duality existing in the same cell is of interest.

dendritic cell (DC). The outcome of the ensuing battle will determine whether the infection will remain locally limited within the engulfing cells of the innate immune system, or will continue to spread, causing the individual to become a clinically active TB patient [1,6,7,8]. During the first contact, the AMac recognizes the microbe through pattern recognition receptors (PRRs), which sense microbial biochemical components, such as outer coat manno‐ sylated lipoarabinomannan (ManLam), trehalose dimycolate and N-glycolymuramyl dipep‐ tide. These molecules act as pathogen-associated molecular patterns (PAMPs), which trigger an intracellular signaling cascade in the AMac, which leads to a phagocytic activity, which, if successful, will result into the complete engulfing of the microbe into cytosolic vesicles- the phagolysozomes and secretion of pro-inflammatory cytokines, such as tumor-necrosis factor alpha (TNFα). ManLam also binds directly to mannose receptors on macrophages and DCs.

The best studied PRRs are Toll-like receptors (TLRs) [6,9,10], of which 10 have been identified in humans. TLR- 2 and TLR-4 recognize bacterial products [9,11], TLR-2 having a major role in recognizing MTB in the lung. All contain an intracellular TIR domain, the activation of which initiates a signaling cascade via adapter proteins such as MyD88, interferon-inducing TRIF and TRIF-related adapter molecule TRAM, which results in the recruitment of interleu‐ kin-1(IL-1) receptor-associated kinase (IRAK) 4, which phosphorylates IRAK-1. The latter binds to TNFα receptor-associated factor (TRAF) 6, leading to kinase-dependent IkBα phosphorylation, the degradation of which leads to the activation of nuclear NF-kB, which is the main nuclear activator of proinflammatory cytokines. Another intracellular PRR is nucleotide-binding oligomerization domain 2 (NOD2), which binds bacterial cell-wall muramyl-dipeptide, eliciting secretion of TNFα, IL-1β, IL-6 and bacteridal LL-37 [12,13]

Neutrophils also play a defensive role, not only as first-line non-specific phagocytes, but also by secreting anti-bacterial proteins, mainly the cathelicidin LL-37 [1,14]. Neutrophils loaded by phagocytized bacteria become apoptotic, thereby eliciting macrophage activation [15].

NK cells, which are large granular circulating lymphocytes, are attracted to the sites of bacterial infections, where they specialize in recognizing and destroying infected host cells. During this process they secrete interferon gamma (IFNγ), which activates macrophages, inducing them to secrete the cytokines IL-12, IL-15 and IL-18, which activate CD8+T-cells, thus forming the

The complement is the humoral arm of the innate immune system. It has been shown that M. bovis BCG may activate the three pathways of complement: the classical pathway by binding to the C1q protein, the lectin pathway by binding to the bacterial cell surface mannose-binding lectin (MBL) or L-ficolin and the alternate pathway through the deposition of C3b on the bacterial surface. Mtb can activate the classical and alternate pathways by binding C3. This enables complement to perform its major functions-microbial opsonization, microbial cell lysis through the formation of the attack complex and leukocyte recruitment by eliciting chemokine

Another recently discovered anti-microbial mechanism of phagocytic cells is the use of vital transition metals, such as iron, zinc and copper, to poison intracellular microorganisms. However, mycobacteria have developed a resistance mechanism to such intoxication [18,19].

link to the adaptive immune system [7,16]

20 Tuberculosis - Current Issues in Diagnosis and Management

secretion [7,17].

Virulent Mtbs have acquired the capability to dampen the activity of NF-Kb by some of their antigens [6,7], such as ESAT-6 and ManLam. The latter also inhibits the secretion of IL-12, an essential cytokine in the anti-MTB inflammatory response. ESAT-6 downregulates MyD88- IRAK 4 interaction, thereby also interfering with TLR signaling to NFkB. A third antigen-CFP-10 markedly reduces nitric oxide (NO) and reactive-oxygen species (ROS) production by the macrophages, thereby inhibiting their non-specific killing ability. The microbe may also regulate macrophage apoptosis to its advantage and to inhibit IFNγ- mediated macrophage activation [7]. ESX is a recently discovered protein transport system through the outer membrane of the microbe, which is essential for its survival. It has been demonstrated, in an experimental model, that ESX-5 may modulate macrophage reactivity by dampening the inflammasome activation [21]. These mechanisms enable the microbe to survive in the macrophage phagosome in a balance which is precarious to the host. In addition Mtb may escape the phagolysozome into the cytosol by damaging its membrane. Most recently it has been described that the microbe may secrete toxins, such as the newly discovered MtpA protein, through its outer membrane into the macrophage cytosol, which may cause the death of the later by cell necrosis [22].

Vitamin D seems also to play an important role in the microbe-host pull-of-arms [23]. It may modulate the inflammatory effect of some metalloproteinases (MMPs) in the lung [24] and Vitamin D supplementation has hastened bacterial eradication in pulmonary tuberculosis in a clinical trial [25].

Thus, the encounter between MTB and the various components of the innate immune system induce a complicated and sophisticated series of host responses and counter responses by the microbe. The later is one of the most ancient human infections, carried by our ancestors since they fanned-out from Africa across the globe, therefore enabling it to adapt to the human immune response (26-Cole S, Tuberculosis in time and space, Econference).

However, the next long-term phase of the encounter is played by the activation of the adaptive immune system, as described in the next section.
