Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.7/868
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dc.contributor.authorReddy, Vineel P.-
dc.contributor.authorChinta, Krishna C.-
dc.contributor.authorSaini, Vikram-
dc.contributor.authorGlasgow, Joel N.-
dc.contributor.authorHull, Travis D.-
dc.contributor.authorTraylor, Amie-
dc.contributor.authorRey-Stolle, Fernanda-
dc.contributor.authorSoares, Miguel P.-
dc.contributor.authorMadansein, Rajhmun-
dc.contributor.authorRahman, Md Aejazur-
dc.contributor.authorBarbas, Coral-
dc.contributor.authorNargan, Kievershen-
dc.contributor.authorNaidoo, Threnesan-
dc.contributor.authorRamdial, Pratistadevi K.-
dc.contributor.authorGeorge, James F.-
dc.contributor.authorAgarwal, Anupam-
dc.contributor.authorSteyn, Adrie J. C.-
dc.identifier.citationReddy VP, Chinta KC, Saini V, Glasgow JN, Hull TD, Traylor A, Rey-Stolle F, Soares MP, Madansein R, Rahman MA, Barbas C, Nargan K, Naidoo T, Ramdial PK, George JF, Agarwal A and Steyn AJC (2018) Ferritin H Deficiency in Myeloid Compartments Dysregulates Host Energy Metabolism and Increases Susceptibility to Mycobacterium tuberculosis Infection. Front. Immunol. 9:860. doi: 10.3389/fimmu.2018.00860pt_PT
dc.descriptionThis deposit is composed by the main article plus the supplementary materials of the publication.pt_PT
dc.descriptionThis deposit is composed by a publication in which the IGC's authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.frontiersin.org/articles/10.3389/fimmu.2018.00860/fullpt_PT
dc.description.abstractIron is an essential factor for the growth and virulence of Mycobacterium tuberculosis (Mtb). However, little is known about the mechanisms by which the host controls iron availability during infection. Since ferritin heavy chain (FtH) is a major intracellular source of reserve iron in the host, we hypothesized that the lack of FtH would cause dysregulated iron homeostasis to exacerbate TB disease. Therefore, we used knockout mice lacking FtH in myeloid-derived cell populations to study Mtb disease progression. We found that FtH plays a critical role in protecting mice against Mtb, as evidenced by increased organ burden, extrapulmonary dissemination, and decreased survival in Fth−/− mice. Flow cytometry analysis showed that reduced levels of FtH contribute to an excessive inflammatory response to exacerbate disease. Extracellular flux analysis showed that FtH is essential for maintaining bioenergetic homeostasis through oxidative phosphorylation. In support of these findings, RNAseq and mass spectrometry analyses demonstrated an essential role for FtH in mitochondrial function and maintenance of central intermediary metabolism in vivo. Further, we show that FtH deficiency leads to iron dysregulation through the hepcidin–ferroportin axis during infection. To assess the clinical significance of our animal studies, we performed a clinicopathological analysis of iron distribution within human TB lung tissue and showed that Mtb severely disrupts iron homeostasis in distinct microanatomic locations of the human lung. We identified hemorrhage as a major source of metabolically inert iron deposition. Importantly, we observed increased iron levels in human TB lung tissue compared to healthy tissue. Overall, these findings advance our understanding of the link between iron-dependent energy metabolism and immunity and provide new insight into iron distribution within the spectrum of human pulmonary TB. These metabolic mechanisms could serve as the foundation for novel host-directed strategies.pt_PT
dc.description.sponsorshipThis work was supported by NIH grants R01AI111940, R21AI127182, a Bill and Melinda Gates Foundation Award (OPP1130017) (to AJCS), DK59600 and DK079337 (to AA) and pilot funds from the UAB Centers for AIDS Research and Free Radical Biology, and UAB School of Medicine Infectious Diseases and Global Health and Vaccines Initiative to AJCS. The research was also co-funded by the South African Medical Research Council to AJCS. This publication is also based on worksupported by a grant from the U.S. Department of Agriculture. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the U.S. Department of Agriculture. Support by Fundação para a Ciência e Tecnologia grants PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, European Community seventh Framework Grant ERC-2011-AdG 294709-DAMAGE CONTROL (to MPS).pt_PT
dc.publisherFrontiers Mediapt_PT
dc.subjectferritin H chainpt_PT
dc.subjectenergy metabolismpt_PT
dc.titleFerritin H Deficiency in Myeloid Compartments Dysregulates Host Energy Metabolism and Increases Susceptibility to Mycobacterium tuberculosis Infectionpt_PT
degois.publication.titleFrontiers in Immunologypt_PT
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