Temporal modulation of host aerobic glycolysis determines the outcome of Mycobacterium marinum infection.

Abstract

Macrophages are the first-line host defense that the invading Mycobacterium tuberculosis (Mtb) encounters. It has been recently reported that host aerobic glycolysis was elevated post the infection by a couple of virulent mycobacterial species. However, whether this metabolic transition is required for host defense against intracellular pathogens and the underlying mechanisms remain to be further investigated. A pathogenic mycobacterial species, M. marinum, is genetically close to Mtb and was utilized in this study. Through analyzing cellular carbon metabolism of RAW 264.7 (a murine macrophage-like cell line) post M. marinum infection, a strong elevation of glycolysis was observed. Next, three glycolysis inhibitors were examined for their ability to inhibit mycobacterial proliferation inside RAW264.7 macrophages. Among them, a glucose analog, 2-deoxyglucose (2-DG) displayed a protective role against mycobacterial infection. Treatment with 2-DG at concentrations of 0.5 or 1 mM significantly induced autophagy and decreased the phagocytosis of M. marinum by macrophages. Moreover, 2-DG pre-treatment exerted a significantly protective effect on zebrafish larvae by limiting the proliferation of M. marinum, and such effect was correlated to tumor necrosis factor alpha (TNF-α) as the 2-DG pre-treatment increased the expression of TNF-α in both mouse peritoneal macrophages and zebrafish. On the contrary, the 2-DG treatment post infection did not restrain proliferation of M. marinum in WT zebrafish, and even accelerated bacterial replication in TNF-α-/- zebrafish. Together, modulation of glycolysis prior to infection boosts host immunity against M. marinum infection, indicating a potential intervention strategy to control mycobacterial infection.

• Authors: Yuanqing Kan, Lu Meng, Lingling Xie, Lixia Liu, Wenyue Dong, Jintao Feng, Yuchen Yan, Chao Zhao, Gang Peng, Decheng Wang, Mingfang Lu, Chen Yang, Chen Niu
• Journal: Fish & shellfish immunology (Fish Shellfish Immunol) Vol. 96 Pg. 78-85 (Jan 2020) ISSN: 1095-9947 [Electronic] England
• PMID: 31775059 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Topics

• Aerobiosis
• Animals
• Fish Diseases (metabolism, microbiology)
• Glycolysis
• Mice
• Mycobacterium Infections, Nontuberculous (metabolism, microbiology, veterinary)
• Mycobacterium marinum (physiology)
• RAW 264.7 Cells
• Zebrafish