Tuberculosis and the art of macrophage manipulation

Abstract

Macrophages are first-line responders against microbes. The success of Mycobacterium tuberculosis (Mtb) rests upon its ability to convert these antimicrobial cells into a permissive cellular niche. This is a remarkable accomplishment, as the antimicrobial arsenal of macrophages is extensive. Normally bacteria are delivered to an acidic, degradative lysosome through one of several trafficking pathways, including LC3-associated phagocytosis (LAP) and autophagy. Once phagocytozed, the bacilli are subjected to reactive oxygen and nitrogen species, and they induce the expression of proinflammatory cytokines, which serve to augment host responses. However, Mtb hijacks these host defense mechanisms, manipulating host cellular trafficking, innate immune responses, and cell death pathways to its benefit. The complex series of measures and countermeasures between host and pathogen ultimately determines the outcome of infection. In this review, we focus on the diverse effectors that Mtb uses in its multipronged effort to subvert the innate immune responses of macrophages. We highlight recent advances in understanding the molecular interface of the Mtb-macrophage interaction.

Figure 1.

Mtb effectors manipulate host lysosomal trafficking. (A) Mtb and BCG impair lysosomal trafficking. Complex glycolipids in the mycobacterial cell wall such as PIM and ManLAM can impair acquisition of PI3P and alter RAB protein dynamics. Early endosomal RAB proteins (RAB5, RAB22A, RAB14) are retained, and recruitment of activated RAB7 is impaired. (B) Mtb permeabilizes the phagosome, which depends upon EsxA and PDIM. This promotes host defense by activating cytosolic sensors and autophagy, and also allows bacterial effectors to gain access to the cytosol. (C) Once bacterial effectors enter the cytoplasm, they further inhibit host pathways. SapM hydrolyzes PI3P, and PtpA, NdkA, CpsA and EsxG-EsxH target proteins involved in lysosomal trafficking, including the V-ATPase, VPS33B, RAB7, NADPH oxidase and HRS/ESCRT. Addition effectors manipulate inflammasome signaling and IL-1β production. Host proteins are shown in grey, whereas bacterial protein effectors are in red and bacterial lipids are magenta. The action (activating or inhibitory arrow) of the bacterial or host factor is also shown in red or blue, respectively.