Chapter 3 : Pathogenesis of

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This chapter explores the genetic toolbox available for the study of physiology, the immunology relating to infection, and relevant animal models to probe the corresponding disease course. The development of better vaccines is contingent on an understanding of the mechanisms by which evades the innate and adaptive immune responses. A primary tuberculosis (TB) infection in humans generally results from the inhalation of a small number of bacilli. These bacteria are deposited in the lungs and are taken up by alveolar macrophages and dendritic cells (DC). is moderately resistant to many forms of reactive oxygen intermediates (ROI) due to the expression of typical detoxification enzymes, such as superoxide dismutase and catalase-peroxidase-peroxinitrase (KatG). Transmission electron microscopy experiments performed in the late 1960s by D’Arcy Hart suggested that resides within tightly associated membranous vacuoles that fail to fuse with lysosomes. Programmed cell death has a role in controlling mycobacterial replication, as decreases in the bacterial burden are correlated with macrophage cell death. Infected cells are detected by T cells through the recognition of antigens presented on major histocompatibility complex class II (MHC-II) molecules by the receptor on the CD4 T cells, leading to the initiation of the bactericidal activity of macrophages. The immune-system evasion mechanisms of are fundamental for the success of the pathogen, and a clearer understanding of these processes will advance vaccine and chemotherapy development.

Citation: Larsen M, Dao D, Baughn A, Jalapthy K, Jacobs, Jr. W. 2007. Pathogenesis of , p 31-50. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch3

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Major Histocompatibility Complex Class II
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Immune-system evasion and persistence mechanisms of . For to establish a niche in macrophages, cellular antimicrobial pathways must be either disengaged or deactivated. Many macrophage bactericidal pathways are disrupted following infection with . These include killing by reactive nitrogen or oxygen radicals, killing by the acidification of phagosomes, and destruction by the acid hydrolases of the lysosome. Along with evading killing, ensures a reservoir for replication by preventing macrophage cell death and induces cell survival signaling pathways. Persistence in macrophages is mediated through the acquisition of nutrients from the host. Infected macrophages escape recognition by T cells as a result of the -mediated down regulation of class II molecules. The activation of CD8 CTLs is dampened by the -induced blockade of cellular apoptosis. Cytokines shape the development of the host immune response. interferes with the production of protective cytokines by macrophages. The progression of disease follows the dissemination of the tubercle bacteria as a result of -induced macrophage necrosis. TAP, transporters associated with antigen processing.

Citation: Larsen M, Dao D, Baughn A, Jalapthy K, Jacobs, Jr. W. 2007. Pathogenesis of , p 31-50. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch3
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genes involved in immune-system evasion

Citation: Larsen M, Dao D, Baughn A, Jalapthy K, Jacobs, Jr. W. 2007. Pathogenesis of , p 31-50. In Brogden K, Minion F, Cornick N, Stanton T, Zhang Q, Nolan L, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815851.ch3

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