CONTROLLING M.TB: A BALANCE OF IMMUNITY AND IMMUNOPATHOLOGY

Abstract

Pulmonary tuberculosis (TB) remains the third leading infectious killer worldwide. It is estimated that tuberculosis latently infects one third of the world’s population and is responsible for 1.4 million deaths annually. Mycobacterium tuberculosis (M.tb), the bacteria species responsible for tuberculosis, is unique in its ability to evade and survive within the infected host for many years and in some cases the lifetime of the host. The ability of M.tb to survive within the host is linked to its ability to evade the host immune response. Following infection there is the establishment of a dynamic equilibrium between bacterial load and active immunity. Central to the establishment of this dynamic equilibrium and survival of the host is the formation of the pulmonary type I ‘immune’ granuloma. The granuloma is composed of a loose association of innate and adaptive immune cells, where infected macrophages are restricted and contained by activated T cells. The ability of the host to maintain this dynamic equilibrium is responsible for the long-term control of M.tb seen in the majority of infected hosts. However, only a small shift in immune activation can detrimentally alter this delicate balance leading to the development of active TB disease. A number of factors have been identified which enhance an individual’s risk for disease reactivation. Some such risk factors include the acquisition of HIV-AIDS, exposure of cigarette smoke, and the neutralization of TNF, a key cytokine required for anti-TB immunity. Within this thesis we will investigate the underlying mechanisms associated with the establishment of the granuloma, as well as its disruption following cigarette smoke exposure and in the absence of TNF.