pharmaceuticals Review Iron Supplementation Therapy, A Friend and Foe of Mycobacterial Infections? Rafiou Agoro 1,* and Catherine Mura 2,* 1 Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN 46202, USA 2 Experimental and Molecular Immunology and Neurogenetics (INEM), Mixed Research Unit UMR7355, National Center for Scientific Research and Orléans University, 45071 Orléans, France * Correspondence: [email protected] (R.A); [email protected] (C.M.); Tel.: +1-317-278-6140 (R.A.); +33-2-3825-7975 (C.M.) Received: 28 April 2019; Accepted: 15 May 2019; Published: 17 May 2019 Abstract: Iron is an essential element that is required for oxygen transfer, redox, and metabolic activities in mammals and bacteria. Mycobacteria, some of the most prevalent infectious agents in the world, require iron as growth factor. Mycobacterial-infected hosts set up a series of defense mechanisms, including systemic iron restriction and cellular iron distribution, whereas mycobacteria have developed sophisticated strategies to acquire iron from their hosts and to protect themselves from iron’s harmful effects. Therefore, it is assumed that host iron and iron-binding proteins, and natural or synthetic chelators would be keys targets to inhibit mycobacterial proliferation and may have a therapeutic potential. Beyond this hypothesis, recent evidence indicates a host protective effect of iron against mycobacterial infections likely through promoting remodeled immune response. In this review, we discuss experimental procedures and clinical observations that highlight the role of the immune response against mycobacteria under various iron availability conditions. In addition, we discuss the clinical relevance of our knowledge regarding host susceptibility to mycobacteria in the context of iron availability and suggest future directions for research on the relationship between host iron and the immune response and the use of iron as a therapeutic agent. Keywords: iron; mycobacteria; immunity 1. General Context Mycobacterial infections in human populations are increasing worldwide and remain a major cause of morbidity and mortality, making them a major public health concern. The emergence and spread of multi-drug resistant (MDR) and extensively drug-resistant (XDR) mycobacterial strains have shifted our interest to explore new therapeutic approaches. Iron plays a crucial role in the pathophysiology of mycobacteria and should be of great interest for future therapeutic strategies. In this context, the development of an effective iron-based therapy requires a detailed understanding of the role of iron during mycobacterial infections as a target involved in the resistance and/or susceptibility of host. 2. Mycobacteria: The Smart Pathogens The genus Mycobacterium comprises more than 150 species that reside in a wide variety of habitats [1]. These bacteria are typically characterized by the structure of their cell envelope (see Figure1 representing the structure of mycobacterial envelope and for review [2]). Mycobacteria are divided into three groups, the Mycobacterium tuberculosis complex (M. tuberculosis, M. africanum, M. bovis, M. canetti, and M. microti), lepromatous mycobacteria (Mycobacterium leprae), and non-tuberculosis mycobacteria Pharmaceuticals 2019, 12, 75; doi:10.3390/ph12020075 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2019, 12, 75 2 of 28 Pharmaceuticals 2019, 12, x FOR PEER REVIEW 2 of 28 (NTM),tuberculosis a group mycobacteria which contains (NTM), only a group a few pathogenicwhich contains species only involved a few pathogenic mostly in lungspecies infection involved in immunocompromisedmostly in lung infection individuals in immunocompromised [3,4]. individuals [3,4]. FigureFigure 1. SchematicSchematic representation representation of the of thecell envelope cell envelope of Mycobacterium of Mycobacterium tuberculosis tuberculosis (adapted(adapted from [2]). fromThe cell [2]). envelope The cell of envelopeM. tuberculosis of M. includes tuberculosis an innerincludes cell membrane an inner cell(CM), membrane a network (CM), of peptidoglycan a network of(PG) peptidoglycan with covalently (PG) attached with covalently macromolecules: attached AG, macromolecules: PIM2, PIM6, LM, AG, and PIM Man-LAM;2, PIM6, LM,an outer and Man-LAM;membrane (OM) an outer composed membrane of mycolic (OM) acid composed (MA), attached of mycolic to TDM, acid DAT, (MA), PAT, attached PDIM, to and TDM, SL-1; DAT, and PAT,an outmost PDIM, andlayer SL-1; of polysacchari and an outmostdes and layer proteins. of polysaccharides AG: arabinogalac and proteins.tan; DAT: AG: diacyltrehalose; arabinogalactan; LM: DAT:lipomannan; diacyltrehalose; Man-LAM:LM: mannose-capped lipomannan; lipoara Man-LAM:binomannan; mannose-capped PAT: poliacyltrehalose; lipoarabinomannan; PDIM: PAT: poliacyltrehalose; PDIM: phthiocerol dimycocerosate; PIM : phospho-myo-inositol-dimannoside; phthiocerol dimycocerosate; PIM2: phospho-myo-inositol-dimannoside;2 PIM6: phospho-myo-inositol- PIMhexamannoside;6: phospho- MmpL:myo-inositol-hexamannoside; mycobacterial membrane MmpL: protein mycobacterial large; TDM: trehalose membrane dimycolate; protein large;SL-1: TDM:sulphoglycolipid. trehalose dimycolate; SL-1: sulphoglycolipid. Host immune systems have evolved antimicrobial strategies, whereas mycobacteria which are Host immune systems have evolved antimicrobial strategies, whereas mycobacteria which are facultative intracellular pathogens have developed new ways to survive in previously inaccessible facultative intracellular pathogens have developed new ways to survive in previously inaccessible niches and hostile environment. The Mycobacterium tuberculosis complex species are mainly restricted niches and hostile environment. The Mycobacterium tuberculosis complex species are mainly restricted to macrophages as host cells and induce a chronic immunopathology. Macrophages internalize to macrophages as host cells and induce a chronic immunopathology. Macrophages internalize mycobacteria by phagocytosis, but only pathogenic mycobacterial species can survive and proliferate mycobacteria by phagocytosis, but only pathogenic mycobacterial species can survive and proliferate inside these cells. In hosts cells, mycobacteria are located in the phagosome and thus exposed inside these cells. In hosts cells, mycobacteria are located in the phagosome and thus exposed to to hostile conditions, such as oxidative stress, hypoxia, and nutrient restriction also known as hostile conditions, such as oxidative stress, hypoxia, and nutrient restriction also known as nutritional immunity. nutritional immunity. The pathogenic mycobacteria have adapted to the hostile environment of the phagosome by The pathogenic mycobacteria have adapted to the hostile environment of the phagosome by entering into a dormant state. Indeed, during chronic infection, M. tuberculosis survives nutrient entering into a dormant state. Indeed, during chronic infection, M. tuberculosis survives nutrient starvation by using the β-oxidation pathway, which allows fatty acids to be utilized as a unique carbon starvation by using the β-oxidation pathway, which allows fatty acids to be utilized as a unique source. Dormant M. tuberculosis cells are characterized by a distinct cell wall lipid content. Indeed the carbon source. Dormant M. tuberculosis cells are characterized by a distinct cell wall lipid content. β-oxidation pathway is a source of phthiocerol dimycocerosates (PDIM), glycolipids diacyltrehalose Indeed the β-oxidation pathway is a source of phthiocerol dimycocerosates (PDIM), glycolipids (DAT), and polyacyltrehalose (PAT), and sulfolipid (SL-1) [2]. To establish residence in macrophages, diacyltrehalose (DAT), and polyacyltrehalose (PAT), and sulfolipid (SL-1) [2]. To establish residence the pathogenic mycobacteria slow down their growth and can lay in a ‘dormant’ state for decades, in macrophages, the pathogenic mycobacteria slow down their growth and can lay in a ‘dormant’ further limiting the risk of destroying their host macrophages and allowing them to survive harsh state for decades, further limiting the risk of destroying their host macrophages and allowing them living conditions. to survive harsh living conditions. 2.1. Host Response to Mycobacteria Through Immune Cell Activation The host sets up a complex immune response involving both innate and adaptive components that are specific to persistent intracellular pathogens. The host often sequesters mycobacteria in an Pharmaceuticals 2019, 12, 75 3 of 28 2.1. Host Response to Mycobacteria Through Immune Cell Activation The host sets up a complex immune response involving both innate and adaptive components that are specific to persistent intracellular pathogens. The host often sequesters mycobacteria in an organized structure named granuloma, composed of center of phagocytic cells surrounded by T and B lymphocytes, that regulates the immune-mediated containment of the infection. Granulomas are hypoxic and nutrient-restricted hostile environments for mycobacteria that contain the infection [5]. In most cases, granulomas do not develop into an active site of infection and can resolve infection or support bacterial survival over long period of time. The resident macrophages phagocytize and eradicate most infecting mycobacteria, preventing the mycobacteria colonization and further mycobacterial infection. Indeed, activated macrophages can induce bacteriostatic and bactericide effect on mycobacteria, but mycobacteria can reside within