title: 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.
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Toulouse, France; Institut de Pharmacologie et de Biologie Structurale, Univer-sité Paul Sabatier, Université de Toulouse, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Neyrolles
authors.forename: Frank
authors.initials: F
authors.lastname: Wolschendorf
authors.forename: Avishek
authors.initials: A
authors.lastname: Mitra
authors.forename: Michael
authors.initials: M
authors.lastname: Niederweis
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use / Q000633:toxicity; D003300:Copper / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D008670:Metals / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D014774:Virulence; D015032:Zinc / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D008670:Metals; D003300:Copper; D007501:Iron; D015032:Zinc
keywords: copper; innate immunity; iron; manganese; nutritional immunity; phagosome; poisoning; zinc