Immune Interference in <i>Mycobacterium tuberculosis</i> Intracellular Iron Acquisition through Siderocalin Recognition of Carboxymycobactins

Hoette, Trisha M.; Clifton, M.C.; Zawadzka, Anna; Holmes, Meg A.; Strong, Roland K.; Raymond, Kenneth N.

doi:10.1021/cb200331g

Cited by 27 publications

(21 citation statements)

References 29 publications

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“…The general recognition mechanism of Scn has been extensively studied and is well understood (22,24,(27)(28)(29)(30)(31)(32)(33). Ligands bind in the highly sculpted protein calyx, where the key interaction is through an aryl group binding in a snug pocket between the side chains of K125 and K134, with electrostatic and cation-π interactions to this ring and neighboring ones mediated by the side chains of R81, K124, and K134 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

Allred

Rupert

Gauny

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin-transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein-ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking of f elements, but through a secondary ligandbased metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of twostage biomimetic platforms for photoluminescence, separation, and transport applications.actinide transport | siderocalin | protein crystallography | luminescence spectroscopy | antenna effect E vents of the last decade have heightened public concern that radionuclides may be released to the environment either deliberately or accidentally (1, 2), with such events potentially leading to the internal contamination of a large number of individuals. The actinides are all highly radioactive, as are some lanthanide fission products, and many of their isotopes decay by alpha particle emission (3). Once internalized, they are distributed to various tissues with patterns that depend on the chemical and physical form of the contaminant in question (4). The densely ionizing alpha particles emitted by actinides when retained can cause tissue damage and induce cancer in target tissues in a dosedependent manner (5). Sufficiently high radionuclide doses may also cause manifestations of acute radiation syndrome. The tissue distribution of an actinide will therefore determine the pattern of injury observed and its radiological and chemical toxicities may lead to serious adverse health effects (6-8). Although they are known to rapidly circulate and deposit into major organs such as bone, liver, or kidney after contamination (6,(8)(9)(10), the specific molecular mechanisms associated with mammalian uptake of these toxic heavy elements remain largely unexplored. Proposed mammalian actinide acquisition and transport mechanisms have typically focused on proteins that use conserved motifs to directly bind the essential elements iron or calcium (6, 8, 10-...

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Section: Resultsmentioning

confidence: 99%

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

Allred

Rupert

Gauny

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although intrinsic tryptophan fluorescence quenching (FQ) has been used extensively to examine SCN binding (5, 8, 19), its susceptibility to spectroscopic interference prevents its use in chemically complex, urine-derived specimens. We therefore developed a different screening assay using a combined LC-DSF approach.…”

Section: Resultsmentioning

confidence: 99%

Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine

Shields-Cutler

Crowley

Miller

et al. 2016

Journal of Biological Chemistry

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In human urinary tract infections, host cells release the antimicrobial protein siderocalin (SCN; also known as lipocalin-2, neutrophil gelatinase-associated lipocalin, or 24p3) into the urinary tract. By binding to ferric catechol complexes, SCN can sequester iron, a growth-limiting nutrient for most bacterial pathogens. Recent evidence links the antibacterial activity of SCN in human urine to iron sequestration and metabolomic variation between individuals. To determine whether these metabolomic associations correspond to functional Fe(III)-binding SCN ligands, we devised a biophysical protein binding screen to identify SCN ligands through direct analysis of human urine. This screen revealed a series of physiologic unconjugated urinary catechols that were able to function as SCN ligands of which pyrogallol in particular was positively associated with high urinary SCN activity. In a purified, defined culture system, these physiologic SCN ligands were sufficient to activate SCN antibacterial activity against Escherichia coli. In the presence of multiple SCN ligands, native mass spectrometry demonstrated that SCN may preferentially combine different ligands to coordinate iron, suggesting that availability of specific ligand combinations affects in vivo SCN antibacterial activity. These results support a mechanistic link between the human urinary metabolome and innate immune function.

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“…Human hosts have proteins that bind bacterial siderophores, preventing bacteria from scavenging host iron. One such human protein is lipocalin 2, which has been shown to bind the M. tuberculosis siderophore carboxymycobactin, potentially protecting the host against mycobacterial infection through iron sequestration (107,108). Three studies found that lipocalin 2 protein added to liquid cultures inhibited mycobacterial growth (52,109,110).…”

Section: Siderophores and Iron Sequestrationmentioning

confidence: 99%

Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host?

Hawn

Matheson

Maley

et al. 2013

Microbiol Mol Biol Rev

133

134

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SUMMARY Treatment of tuberculosis (TB) remains challenging, with lengthy treatment durations and complex drug regimens that are toxic and difficult to administer. Similar to the vast majority of antibiotics, drugs for Mycobacterium tuberculosis are directed against microbial targets. Although more effective drugs that target the bacterium may lead to faster cure of patients, it is possible that a biological limit will be reached that can be overcome only by adopting a fundamentally new treatment approach. TB regimens might be improved by including agents that target host pathways. Recent work on host-pathogen interactions, host immunity, and host-directed interventions suggests that supplementing anti-TB therapy with host modulators may lead to shorter treatment times, a reduction in lung damage caused by the disease, and a lower risk of relapse or reinfection. We undertook this review to identify molecular pathways of the host that may be amenable to modulation by small molecules for the treatment of TB. Although several approaches to augmenting standard TB treatment have been proposed, only a few have been explored in detail or advanced to preclinical and clinical studies. Our review focuses on molecular targets and inhibitory small molecules that function within the macrophage or other myeloid cells, on host inflammatory pathways, or at the level of TB-induced lung pathology.

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Immune Interference in Mycobacterium tuberculosis Intracellular Iron Acquisition through Siderocalin Recognition of Carboxymycobactins

Cited by 27 publications

References 29 publications

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides

Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine

Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host?

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