Iron acquisition by Mycobacterium tuberculosis residing within myeloid dendritic cells

Olakanmi, Oyebode; Kesavalu, Banurekha; Abdalla, Maher Y.; Britigan, Bradley E.

doi:10.1016/j.micpath.2013.09.002

Cited by 17 publications

(17 citation statements)

References 43 publications

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“…The ability of intracellular M. tuberculosis to proliferate in DCs remains poorly characterised. Some studies have described intracellular growth [ 38 - 40 ] in DCs, while others have reported only static bacterial loads [ 29 , 30 ]. To clarify these contradictory observations, and to place the results of the library selection in context, we examined the dynamics of the M. tuberculosis library during the DC infection.…”

Section: Resultsmentioning

confidence: 99%

Lipid metabolism and Type VII secretion systems dominate the genome scale virulence profile of Mycobacterium tuberculosis in human dendritic cells

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Kierzek

et al. 2015

BMC Genomics

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BackgroundMycobacterium tuberculosis continues to kill more people than any other bacterium. Although its archetypal host cell is the macrophage, it also enters, and survives within, dendritic cells (DCs). By modulating the behaviour of the DC, M. tuberculosis is able to manipulate the host’s immune response and establish an infection. To identify the M. tuberculosis genes required for survival within DCs we infected primary human DCs with an M. tuberculosis transposon library and identified mutations with a reduced ability to survive.ResultsParallel sequencing of the transposon inserts of the surviving mutants identified a large number of genes as being required for optimal intracellular fitness in DCs. Loci whose mutation attenuated intracellular survival included those involved in synthesising cell wall lipids, not only the well-established virulence factors, pDIM and cord factor, but also sulfolipids and PGL, which have not previously been identified as having a direct virulence role in cells. Other attenuated loci included the secretion systems ESX-1, ESX-2 and ESX-4, alongside many PPE genes, implicating a role for ESX-5. In contrast the canonical ESAT-6 family of ESX substrates did not have intra-DC fitness costs suggesting an alternative ESX-1 associated virulence mechanism. With the aid of a gene-nutrient interaction model, metabolic processes such as cholesterol side chain catabolism, nitrate reductase and cysteine-methionine metabolism were also identified as important for survival in DCs.ConclusionWe conclude that many of the virulence factors required for survival in DC are shared with macrophages, but that survival in DCs also requires several additional functions, such as cysteine-methionine metabolism, PGLs, sulfolipids, ESX systems and PPE genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1569-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Lipid metabolism and Type VII secretion systems dominate the genome scale virulence profile of Mycobacterium tuberculosis in human dendritic cells

Mendum

Kierzek

et al. 2015

BMC Genomics

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“…Similar observations have been made with other intracellular pathogens such as Chlamydia spp. or Legionella (Chlosta et al, 2006; Paradkar et al, 2008; Bellmann-Weiler et al, 2010) Of interest, ferroportin is also expressed in mycobacteria containing phagosomes where it pumps iron into the cytoplasma (Van Zandt et al, 2008), a pathway which limits the availability of this essential nutrient for this bacterium (Schnappinger et al, 2003; Olakanmi et al, 2013). This indicates that the stimulation of iron export via ferroportin is an efficient defense strategy against infection with intracellular microbes by limiting their access to iron and by strengthening anti-microbial immune effector pathways (Nairz et al, 2010).…”

Section: Metabolic Iron Responses and Immune Control Of Intracellularmentioning

confidence: 99%

Iron at the interface of immunity and infection

et al. 2014

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Both, mammalian cells and microbes have an essential need for iron, which is required for many metabolic processes and for microbial pathogenicity. In addition, cross-regulatory interactions between iron homeostasis and immune function are evident. Cytokines and the acute phase protein hepcidin affect iron homeostasis leading to the retention of the metal within macrophages and hypoferremia. This is considered to result from a defense mechanism of the body to limit the availability of iron for extracellular pathogens while on the other hand the reduction of circulating iron results in the development of anemia of inflammation. Opposite, iron and the erythropoiesis inducing hormone erythropoietin affect innate immune responses by influencing interferon-gamma (IFN-γ) mediated (iron) or NF-kB inducible (erythropoietin) immune effector pathways in macrophages. Thus, macrophages loaded with iron lose their ability to kill intracellular pathogens via IFN-γ mediated effector pathways such as nitric oxide (NO) formation. Accordingly, macrophages invaded by the intracellular bacterium Salmonella enterica serovar Typhimurium increase the expression of the iron export protein ferroportin thereby reducing the availability of iron for intramacrophage bacteria while on the other side strengthening anti-microbial macrophage effector pathways via increased formation of NO or TNF-α. In addition, certain innate resistance genes such as natural resistance associated macrophage protein function (Nramp1) or lipocalin-2 exert part of their antimicrobial activity by controlling host and/or microbial iron homeostasis. Consequently, pharmacological or dietary modification of cellular iron trafficking enhances host resistance to intracellular pathogens but may increase susceptibility to microbes in the extracellular compartment and vice versa. Thus, the control over iron homeostasis is a central battlefield in host–pathogen interplay influencing the course of an infectious disease in favor of either the mammalian host or the pathogenic invader.

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“…Our lab and others have shown that M. tuberculosis replicating in human macrophages can acquire Fe bound to transferrin or lactoferrin and from exogenous sources (13)(14)(15)(16). Fe is an important component of enzymes involved in critical cellular functions such as DNA synthesis (17), general metabolism, and oxidative stress resistance.…”

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confidence: 99%

Gallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus

Abdalla

Switzer

Goss

et al. 2015

Antimicrob Agents Chemother

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The rapidly growing nontuberculous mycobacterial species Mycobacterium abscessus has recently emerged as an important pathogen in patients with cystic fibrosis (CF). Treatment options are limited because of the organism's innate resistance to standard antituberculous antibiotics, as well as other currently available antibiotics. New antibiotic approaches to the treatment of M. abscessus are urgently needed. The goal of the present study was to assess the growth-inhibitory activity of different Ga compounds against an American Type Culture Collection (ATCC) strain and clinical isolates of M. abscessus obtained from CF and other patients. In our results, using Ga(NO 3 ) 3 and all of the other Ga compounds tested inhibited the growth of ATCC 19977 and clinical isolates of M. abscessus. Inhibition was mediated by disrupting iron uptake, as the addition of exogenous iron (Fe) restored basal growth. There were modest differences in inhibition among the isolates for the same Ga chelates, and for most Ga chelates there was only a slight difference in potency from Ga(NO 3 ) 3 . In contrast, Ga-protoporphyrin completely and significantly inhibited the ATCC strain and clinical isolates of M. abscessus at much lower concentrations than Ga(NO 3 ) 3 . In in vitro broth culture, Ga-protoporphyrin was more potent than Ga(NO 3 ) 3 . When M. abscessus growth inside the human macrophage THP-1 cell line was assessed, Ga-protoporphyrin was >20 times more active than Ga(NO 3 ) 3 . The present work suggests that Ga exhibits potent growth-inhibitory capacity against the ATCC strain, as well as against antibiotic-resistant clinical isolates of M. abscessus, including the highly antibiotic-resistant strain MC2638. Ga-based therapy offers the potential for further development as a novel therapy against M. abscessus.

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Iron acquisition by Mycobacterium tuberculosis residing within myeloid dendritic cells

Cited by 17 publications

References 43 publications

Lipid metabolism and Type VII secretion systems dominate the genome scale virulence profile of Mycobacterium tuberculosis in human dendritic cells

Lipid metabolism and Type VII secretion systems dominate the genome scale virulence profile of Mycobacterium tuberculosis in human dendritic cells

Iron at the interface of immunity and infection

Gallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus

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