Mycobacterial survival strategies in the phagosome: defence against host stresses

Abstract

Infections with Mycobacterium tuberculosis remain a major cause of disease and death in humans. Among the factors that contribute to M. tuberculosis's success as a pathogen is its ability to withstand potentially bactericidal host defences and to resist elimination by an activated immune system. This resistance to killing by the host is in part due to the low permeability of the mycobacterial cell envelope for many toxic molecules. In addition, it depends upon the detoxification of reactive oxygen and reactive nitrogen molecules produced by the host, the repair of the damage these molecules cause and maintenance of a neutral intrabacterial pH within acidic environments. The latter three mechanisms are the focus of this review.

Figure 1

Mycobacterium tuberculosis (Mtb) inside the macrophage. In resting macrophages, Mtb stalls phagosome maturation and inhibits phagolysosome fusion. As a consequence, Mtb resides in a mildly acidic compartment and is exposed to reactive oxygen intermediates (ROI) from phagocyte oxidase (NOX2). Upon immunological activation with IFNγ the phagosome matures and fuses with lysosomes. This exposes Mtb to protons from the vacuolar ATPase, reactive nitrogen intermediates (RNI) from inducible nitric oxide synthase (iNOS) and ROI from NOX2. Mtb has evolved mechanisms to counter these interdependent forms of stress and allow its survival within the acidic, nitro-oxidative phagolysosome of activated macrophages.