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The interaction of M. tuberculosis with the human host begins when droplet nuclei containing viable microorganisms, propelled into the air by infectious patients, are inhaled by a close bystander. Although the majority of inhaled bacilli are trapped in the upper airways and expelled by ciliated mucosal cells, a fraction (usually <10%) reach the alveoli, a unique immunoregulatory environment. There, alveolar macrophages that have not yet been activated (prototypic alternatively activated macrophages) phagocytose the bacilli. Adhesion of mycobacteria to macrophages results largely from binding of the bacterial cell wall to a variety of macrophage cell-surface molecules, including complement receptors, the mannose receptor, the immunoglobulin G Fcγ receptor, and type A scavenger receptors. Surfactants may also play a role in the early phase of interaction between the host and the pathogen, and surfactant protein D can prevent phagocytosis. Phagocytosis is enhanced by complement activation leading to opsonization of bacilli with C3 activation products such as C3b and C3bi. (Bacilli are resistant to complement-mediated lysis.) Binding of certain receptors, such as the mannose receptor, regulates postphagocytic events such as phagosome–lysosome fusion and inflammatory cytokine production. After a phagosome forms, the survival of M. tuberculosis within it seems to depend in part on reduced acidification due to lack of assembly of a complete vesicular proton-adenosine triphosphatase. A complex series of events is generated by the bacterial cell-wall lipoglycan lipoarabinomannan, which inhibits the intracellular increase of Ca2+. Thus, the Ca2+/calmodulin pathway (leading to phagosome–lysosome fusion) is impaired, and the bacilli survive within the phagosomes by blocking fusion. The M. tuberculosis phagosome inhibits the production of phosphatidylinositol 3-phosphate, which normally earmarks phagosomes for membrane sorting and maturation (including phagolysosome formation), which would destroy the bacteria. Bacterial factors block the host defense of autophagy, in which the cell sequesters the phagosome in a double-membrane vesicle (autophagosome) that is destined to fuse with lysosomes. If the bacilli are successful in arresting phagosome maturation, then replication begins and the macrophage eventually ruptures and releases its bacillary contents. This process is mediated by the ESX-1 secretion system that is encoded by genes contained in the region of difference 1 (RD1). Other uninfected phagocytic cells are then recruited to continue the infection cycle by ingesting dying macrophages and their bacillary content, thus, in turn, becoming infected themselves and expanding the infection.


image M. tuberculosis must be viewed as a complex formed by a multitude of strains that differ in virulence and are capable of producing a variety of manifestations of disease. Since the elucidation of the M. tuberculosis genome in 1998, large mutant collections have been generated, and many bacterial genes that contribute to M. tuberculosis virulence have been found. Different patterns of virulence defects have been defined in various animal models—predominantly mice but also guinea pigs, rabbits, and nonhuman primates. The katG gene encodes for a catalase/peroxidase enzyme that ...

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