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

Frontiers in Immunology

Md Aejazur Rahman¹  Coral Barbas²  Fernanda Rey-Stolle²  Pratistadevi K. Ramdial³  Kievershen Nargan³  Threnesan Naidoo³  Vikram Saini⁴  Vineel P. Reddy⁴  Krishna C. Chinta⁴  Joel N. Glasgow⁴  James F. George⁵  Travis D. Hull⁵  Rajhmun Madansein⁶  Miguel P. Soares⁷  Amie Traylor⁸  Anupam Agarwal⁸  Adrie J. C. Steyn⁹ 

[1] Africa Health Research Institute (AHRI), Durban, South Africa;Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain;Department of Anatomical Pathology, National Health Laboratory Service, University of KwaZulu-Natal, Inkosi Albert Luthuli Central Hospital, Durban, South Africa;Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States;Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, AL, United States;Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa;Instituto Gulbenkian de Ciência, Oeiras, Portugal;Nephrology Research and Training Center, University of Alabama at Birmingham and Birmingham VA Medical Center, Birmingham, AL, United States;UAB Centers for AIDS Research and Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, United States;

关键词: ferritin H chain;    bioenergetics;    immunometabolism;    tuberculosis;    iron;    energy metabolism;   

DOI  :  10.3389/fimmu.2018.00860

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown