Ferritin H Deficiency in Myeloid Compartments Dysregulates Host Energy Metabolism and Increases Susceptibility to Mycobacterium tuberculosis Infection

Reddy, Vineel P.; Chinta, Krishna C.; Saini, Vikram; Glasgow, Joel N.; Hull, Travis D.; Traylor, Amie; Rey-Stolle, Fernanda; Soares, Miguel P.; Madansein, Rajhmun; Rahman, Md Aejazur; Barbas, Coral; Nargan, Kievershen; Naidoo, Threnesan; Ramdial, Pratistadevi K.; George, James F.; Agarwal, Anupam; Steyn, Adrie J. C.

Publication

Ferritin H Deficiency in Myeloid Compartments Dysregulates Host Energy Metabolism and Increases Susceptibility to Mycobacterium tuberculosis Infection

2018-05-03Journal article

dc.contributor.author	Reddy, Vineel P.
dc.contributor.author	Chinta, Krishna C.
dc.contributor.author	Saini, Vikram
dc.contributor.author	Glasgow, Joel N.
dc.contributor.author	Hull, Travis D.
dc.contributor.author	Traylor, Amie
dc.contributor.author	Rey-Stolle, Fernanda
dc.contributor.author	Soares, Miguel P.
dc.contributor.author	Madansein, Rajhmun
dc.contributor.author	Rahman, Md Aejazur
dc.contributor.author	Barbas, Coral
dc.contributor.author	Nargan, Kievershen
dc.contributor.author	Naidoo, Threnesan
dc.contributor.author	Ramdial, Pratistadevi K.
dc.contributor.author	George, James F.
dc.contributor.author	Agarwal, Anupam
dc.contributor.author	Steyn, Adrie J. C.
dc.date.accessioned	2018-05-16T10:34:12Z
dc.date.available	2018-05-16T10:34:12Z
dc.date.issued	2018-05-03
dc.description	This deposit is composed by the main article plus the supplementary materials of the publication.	pt_PT
dc.description	This 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/full	pt_PT
dc.description.abstract	Iron 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.sponsorship	This 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.description.version	info:eu-repo/semantics/publishedVersion	pt_PT
dc.identifier.citation	Reddy 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.2018.00860	pt_PT
dc.identifier.doi	10.3389/fimmu.2018.00860	pt_PT
dc.identifier.uri	http://hdl.handle.net/10400.7/868
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.publisher	Frontiers Media	pt_PT
dc.relation	R01AI111940	pt_PT
dc.relation	R21AI127182	pt_PT
dc.relation	OPP1130017	pt_PT
dc.relation	DK59600	pt_PT
dc.relation	DK079337	pt_PT
dc.relation	HMSP-ICT/0022/2010	pt_PT
dc.relation	Tissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases
dc.relation.publisherversion	https://www.frontiersin.org/articles/10.3389/fimmu.2018.00860/full	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	pt_PT
dc.subject	ferritin H chain	pt_PT
dc.subject	bioenergetics	pt_PT
dc.subject	immunometabolism	pt_PT
dc.subject	tuberculosis	pt_PT
dc.subject	iron	pt_PT
dc.subject	energy metabolism	pt_PT
dc.title	Ferritin H Deficiency in Myeloid Compartments Dysregulates Host Energy Metabolism and Increases Susceptibility to Mycobacterium tuberculosis Infection	pt_PT
dc.type	journal article
dspace.entity.type	Publication
oaire.awardTitle	Tissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases
oaire.awardURI	info:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-TOX%2F116627%2F2010/PT
oaire.awardURI	info:eu-repo/grantAgreement/EC/FP7/294709/EU
oaire.citation.endPage	23	pt_PT
oaire.citation.startPage	1	pt_PT
oaire.citation.title	Frontiers in Immunology	pt_PT
oaire.citation.volume	9	pt_PT
oaire.fundingStream	3599-PPCDT
oaire.fundingStream	FP7
project.funder.identifier	http://doi.org/10.13039/501100001871
project.funder.identifier	http://doi.org/10.13039/501100008530
project.funder.name	Fundação para a Ciência e a Tecnologia
project.funder.name	European Commission
rcaap.rights	restrictedAccess	pt_PT
rcaap.type	article	pt_PT
relation.isProjectOfPublication	72d8fa6f-1215-4a61-bc70-515eef334d45
relation.isProjectOfPublication	370f9aad-c4ef-4e35-b754-edc840dc6b5e
relation.isProjectOfPublication.latestForDiscovery	370f9aad-c4ef-4e35-b754-edc840dc6b5e