Mycobacteria, metals, and the macrophage

Abstract

Summary Mycobacterium tuberculosis is a facultative intracellular pathogen that thrives inside host macrophages. A key trait of M. tuberculosis is to exploit and manipulate metal cation trafficking inside infected macrophages to ensure survival and replication inside the phagosome. Here we describe the recent fascinating discoveries that the mammalian immune system responds to infections with M. tuberculosis by overloading the phagosome with copper and zinc, two metals which are essential nutrients in small quantities but are toxic in excess. M. tuberculosis has developed multi-faceted resistance mechanisms to protect itself from metal toxicity including control of uptake, sequestration inside the cell, oxidation, and efflux. The host response to infections combines this metal poisoning strategy with nutritional immunity mechanisms that deprive M. tuberculosis from metals such as iron and manganese to prevent bacterial replication. Both immune mechanisms rely on the translocation of metal transporter proteins to the phagosomal membrane during the maturation process of the phagosome. This review summarizes these recent findings and discusses how metal-targeted approaches might complement existing TB chemotherapeutic regimens with novel anti-infective therapies.

Survival in amoeba—a major selection pressure on the presence of bacterial copper and zinc resistance determinants? Identification of a “copper pathogenicity island”

“…Such structures allow accumulation of Zn 2+ in the intracellular organelles followed by its utilization in biological processes specific for a given cell type. In particular, macrophages employ Zn 2+ and Cu + to attack Fe-S clusters essential for bacterial survival (Braymer and Giedroc 2014;Dupont et al 2011;Festa and Thiele 2012;Kashyap et al 2014;Macomber and Imlay 2009;Neyrolles et al 2015;Subashchandrabose et al 2014;Xu and Imlay 2012). We hypothesize that such a mechanism, where bacterial killing occurs through accumulation of Zn 2+ and Cu + in the phagosome/vacuole, originated in protozoa long before multicellular life arose and that it later evolved in eukaryotic phagocytes.…”

Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis

“…The esxG-esxH complementing plasmid (pJP130), described below, was selected with 25 g of kanamycin/ml. For iron and zinc starvation experiments, bacteria were grown in liquid Middlebrook 7H9 medium to logarithmic phase and then subcultured in chelated Sauton's (CS) medium (0.5 g of KH 2 PO 4 , 2 g of citric acid monohydrate, 4 g of asparagine, 1 g of MgSO 4 , 60 ml of glycerol, and 0.05% Tween 80 per liter). After the pH was adjusted to 7.4, Sauton's medium was chelated using 10 g of Chelex 100 (Sigma) over 2 days, after which 1 g of MgSO 4 was added back.…”

“…M. tuberculosis evades degradation by the endolysosomal pathway, growing in an early endosome-like compartment or escaping into the cytosol (2,3). Acidified lysosomes are just one obstacle for the bacilli to overcome as the host also regulates metals such as iron, zinc, copper, and manganese to create an uninhabitable microenvironment (4). These metals are essential but at the same time can be toxic, so both host and pathogen tightly regulate them.…”

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

“…The essential micronutrient manganese and iron are depleted, for example by efflux of iron by Nramp1 [276]. To overcome iron limitation, Mtb chelates iron via capture systems, so-called mycobactins [277] and utilizes heme [278] and binds ironloaded transferrin via specific receptors [173].…”

“…To overcome iron limitation, Mtb chelates iron via capture systems, so-called mycobactins [277] and utilizes heme [278] and binds ironloaded transferrin via specific receptors [173]. Contrary to that, the macrophages 'poisons' the phagosome with zinc and copper ions [279,280], which Mtb counteracts by expressing metal efflux pumps [276]. [163,281,282].…”