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

Frontiers in Immunology
Vineel P ReddyAdrie J C Steyn

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-ferropo...Continue Reading

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Citations

Feb 23, 2019·The Journal of Experimental Medicine·Eduardo P AmaralAlan Sher
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Datasets Mentioned

BETA
GSE112361

Methods Mentioned

BETA
RNAseq
electrophoresis
PCR
bronchoalveolar lavage
bronchoalveolar
lavage
flow cytometry
Assay
ELISA
protein assay

Software Mentioned

Profinder
Mass Hunter Unknown Analysis
Cuffmerge
FlowJo
Systematized Nomenclature of Medicine ( SNOMED )
MetaboAnalyst
MassHunter Quantitative Analysis
Matlab
MetPa
Cufflinks

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