Mycobacteria, metals, and the macrophage

Abstract

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.

Keywords: copper; innate immunity; iron; manganese; nutritional immunity; phagosome; poisoning; zinc.

Fig. 1. Role of metals during infection with M. tuberculosis

CTR1 translocates Cu⁺ from the extracellular space to the cytoplasm of macrophages infected with M. tuberculosis. Then, Cu⁺ is bound by the chaperone ATOX1, which delivers copper to the ATP7A pump resulting in copper accumulation in the phagosome (19, 139, 175, 212). V-type ATPases and an unknown transporter pump protons and Zn²⁺, respectively, into the phagosome (20, 181). NRAMP1 exports Fe²⁺ and Mn²⁺ out of the phagosome. Fe²⁺ is bound by intracellular ferritin (200). The extracellular proteins transferrin sequesters iron, while calprotectin sequesters Mn²⁺ and Zn²⁺ (200). Calprotectin is secreted by neutrophils in tuberculosis granulomas (114) likely to deplete granulomas from Mn²⁺ and Zn²⁺.