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Mycobacterium tuberculosis quickly after infection encounters with alveolar resident macrophages, after which dendritic cells and monocyte-derived macrophages also take part in the phagocytic process.

Transmission of Mycobacterium tuberculosis

Patients, suffering from active pulmonary TB are the principal source of TB transmission. These patients expel aerosolized tubercle bacilli by the respiratory route and may infect any individual, unfortunate enough to inhale the aerosolized bacteria.

Respiratory droplets are generated by human’s coughs and sneezes and they remain airborne for about 6-10 hours.

Thus, approximately one third of the world population, i.e. ~2 billion peoples are latently infected with this etiological pathogen.

Mycobacterium tuberculosis F1

Mycobacterium tuberculosis quickly after infection encounters with alveolar resident macrophages, after which dendritic cells and monocyte-derived macrophages also take part in the phagocytic process.

Although, both pathogenic and non¬pathogenic mycobacteria can enter in macrophages with similar facility, but only the pathogenic species can survive therein.

Replication and dissemination of the pathogen are restricted by mononuclear phagocytes and control the infection by cell-mediated immunity (CMI).

Mycobacterium tuberculosis remains dormant until the balance between bacillary persistence and the immune response gets disturbed.

The infected alveolar macrophages containing the pathogen either destroy their predators (a mechanism that has not yet been proven, but probably accounts for a small proportion), or they fail to contain the pathogen and die.

Immune response and virulence of M. tuberculosis are balanced, intracellular bacteria are contained by the macrophages, and the immune system isolates the primary site of infection by granuloma formation (primary lesion).

Mycobacterium tuberculosis can persist in a dormant state for long periods of time even sometimes lifelong.

"Mycobacterium tuberculosis remains dormant until the balance between bacillary persistence and the immune response gets disturbed"

Any disturbance of the balance between host and pathogen after weakening of the cellular immune response (immuno-suppression) causes endogenous exacerbation which leads to active (post primary) TB.

An impaired host response due to various reasons including aging, malnutrition, steroids or HIV allows reactivation of the bacilli resulting in clinical manifestation of disease.

Understanding the patho-mechanisms of latent persistence of Mycobacterium tuberculosis will therefore facilitate novel approaches towards prevention and control of infection, reactivation and re-infection.

Intracellular multiplication of Mycobacterium tuberculosis in alveolar macropbages

Most alveolar macrophages are highly activated cells capable of destroying or inhibiting the growth of inhaled bacilli, especially if these bacilli are not fully virulent.

However, some alveolar macrophages are poorly activated and allow ingested tubercle bacilli to multiply intracellularly.

Virulent strains of Mycobacterium tuberculosis also uses a variety of strategies to avoid phagosome-lysosome fusion in macrophage and multiply continuously, eventually lead to the lysis of the infected cell.

Mycobacterium tuberculosis F3
Once the bacteria are transported into the deeper tissues by macrophage and perhaps other phagocytic cells, additional macrophages gather at individual infected cell to form granuloma.

The extracellular bacilli are then taken up by other macrophages and by blood monocytes that are attracted to the focus and then develop into immature macrophages.

Thus, the bacillary multiplication cycle is repeated within immature macrophages, which lead to the spread of mycobacteria to deeper tissues and other organs including lymph nodes, where they multiply.

Once the bacteria are transported into the deeper tissues by macrophage and perhaps other phagocytic cells, additional macrophages gather at individual infected cell to form granuloma.

The tuberculous granulomas in humans and mice have a large complement of T lymphocytes, some B lymphocytes, dendritic cells, neutrophils, fibroblasts, and extracellular matrix components.

Although the role of all the accessory cells in the granuloma formation has not yet been clarified, certain T lymphocytes subsets play an unequivocal role in the maintenance of the granuloma and in restriction of the bacterial growth in human infection.

Granuloma formation: Host versus Mycobacteria

Inside the necrotic lesion the tubercle bacilli survive in the solid caseous lesions, but fail to multiply there because of anoxic conditions, reduced pH and the presence of inhibitory fatty acids.

At this stage, the cell mediated immune response gets activated, which initiates the proliferation of T- lymphocytes and macro phages that accumulate around caseous centre to prevent the extension of lesion. Depending on the host, an appropriate immune response can control mycobacterial growth.

Thus, it is of prime importance to define differences in architecture and functional properties of the granuloma. Several studies have shown that the cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) play a key role during the latent phase of infection.

The TNF-α and IL-10 seems to play a role in containing persistent M. tuberculosis and preventing them from reaching other region of the lung or other organs.

Both CD4 and CD8 positive T cells are found mainly in the periphery of intact granulomas, and their total number correlates with the structure integrity of granuloma.

Production of limphotoxin-alpha3 (LT-α3) by CD4 T -cells seems to mediate granuloma formation and maintenance. Reduced numbers of CD4 T -cells in HIV -positive patients are therefore a major risk factor for reactivation of persistent M. tuberculosis.

"Depending on the host, an appropriate immune response can control mycobacterial growth"

The massive activation of macrophages that occurs within tubercles often results in the concentrated release of lytic enzymes.

These enzymes destroy nearby healthy cells; resulting circular regions of necrotic tissue from a necrotic lesion with a caseous.

As these caseous lesions heal, they become calcified and are readily visible on X-rays, where they are called Ghon complexes. The caseous necrosis is the basic process of tuberculosis disease in human.

Protection against Mycobacterium tuberculosis

Elimination of Mycobacterium tuberculosis infection mainly depends on the success of the interaction between infected macrophages and T-Iymphocytes. Primary as well as acquired immunodeficiencies, especially human immunodeficiency virus infection, have dramatically shown the importance of cellular immunity in TB.

CD4+T cells exert their protective effect by the production of cytokines, primarily IFN-γ, after stimulation with mycobacterial antigens.

Other T -cell subsets, like CD8+ T cells, are likely to contribute as well by lysing infected cells.

The acquired T-cell response develops in the context of the major histocompatibility comples (MHC), which may contribute to differences in disease susceptibility or outcome.

"Elimination of M. tuberculosis infection mainly depends on the success of the interaction between infected macrophages and T-Iymphocytes"

In mycobacterial infection, Th I-type cytokines seem to be essential for protective immunity. Indeed. IFN-γ gene knockout (KO) mice are highly susceptible to M.tuberculosis and individuals lacking receptors for IFN-γ suffer from recurrent, sometimes lethal mycobacterial infections.

Th2-type cytokines inhibit the in vitro production of IFN-γ, as well as the activation of macrophages, and may therefore weaken host defense. It has shown an increase in Th2-type cytokines in TB patients.

However, this is not a consistent finding, and the relevance of the Th1-Th2 concept in disease susceptibility or presentation remains uncertain.

Mycobacterium tuberculosis F5

Phagocytic cells play a key role in the initiation and direction of adaptive T-cell immunity by presentation of mycobacterial antigens and expression of costimulatory signals and cytokines.

Activated T cells migrate via the bloodstream to the site(s) of infection, emigrate from the intravascular space into the tissue and deliver macrophage-activating cytokines.

This result in the formation of granuloma and effective cell recruitment must be sustained for the life of the host in order to maintain control of the infection.

More recently it was found that acquired T-cell immunity in vaccinated mice effectively protects them from disseminated tuberculosis but does not prevent the initial pulmonary infection. In human disease, the same holds true.

"Phagocytic cells play a key role in the initiation and direction of adaptive T-cell immunity by presentation of mycobacterial antigens "

Acquired T-cell immunity after vaccination with Mycobacterium bovis BCG is more effective against disseminated infection than against pulmonary disease.

Similarly, naturally acquired T-cell immunity does not prevent exogenous re-infection of the lung. Thus, local, T -cell-independent host defense mechanisms clearly are involved in protection against pulmonary infection.

Immune Response in Tuberculosis

Recognition of Mycobacterium tuberculosis by phagocytic cells leads to cell activation and production of cytokines, which in itself induces further activation and cytokine production in a complex process of regulation and cross-regulation.

This cytokine network plays a crucial role in the inflammatory response and the outcome of mycobacterial infections.

"The IgM antibodies appear in the initial stages followed by rise and persistence of IgG antibodies"

Mycobacterium tuberculosis infection induces humoral response (antibodies) in infected host that are capable of binding to various mycobacterial antigens, majority of antibodies have been found to be directed towards the cell wall antigens.

B cells are recruited to the lungs of mice infected with Mycobacterium tuberculosis and contribute to granuloma formation, yet mice that lack mature B cells are able to control the growth of the bacteria in the lungs.

The observation that B-cell deficient mice recruit fewer neutrophils, macrophages and CD8+ T lymphocytes to their lungs implies a role for B cells in the regulation of chemokine and/or adhesion protein expression after infection with Mycobacterium tuberculosis.

Grange 1984 reported the induction of various classes of immunoglobulins in TB patients to mycobacterial antigens.

The IgM antibodies appear in the initial stages followed by rise and persistence of IgG antibodies.

But their role in providing immunity against Mycobacterium tuberculosis infections suggests that antibodies do not protect the host from TB.

It may be concluded that contribution of antibodies in inducing immunity against Mycobacterium tuberculosis if any is not clear.

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