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

• Published in: Fish & shellfish immunology Vol. 96; pp. 78 - 85
• Main Authors: Kan, Yuanqing, Meng, Lu, Xie, Lingling, Liu, Lixia, Dong, Wenyue, Feng, Jintao, Yan, Yuchen, Zhao, Chao, Peng, Gang, Wang, Decheng, Lu, Mingfang, Yang, Chen, Niu, Chen
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2020
• Subjects: Aerobiosis; Animals; Fish Diseases - metabolism; Fish Diseases - microbiology; Glycolysis; Macrophages; Mice; Mycobacterium Infections, Nontuberculous - metabolism; Mycobacterium Infections, Nontuberculous - microbiology; Mycobacterium Infections, Nontuberculous - veterinary; Mycobacterium marinum; Mycobacterium marinum - physiology; Phagocytosis; RAW 264.7 Cells; Zebrafish; Mycobacterium marinum; FL; Macrophages; HK2; MFI; HDT; MDR; LC3; HPLC; hpf; hpi; G6P; IL; MOI; Zebrafish; 2-DG; RAW cells; ppm; TB; M. marinum; TCA; TNF-α; OADC; Glycolysis; FPC; Mtb; Phagocytosis
• ISSN: 1050-4648; 1095-9947
• DOI: 10.1016/j.fsi.2019.11.051

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. •Macrophages displayed an elevated glycolysis post M. marinum infection.•2-DG reduced phagocytosis and M. marinum burden inside macrophages.•2-DG pretreatment led to autophagy or apoptosis of RAW cells.•2-DG pre-treatment inhibited the proliferation of M. marinum in WT zebrafish.•2-DG accelerated M. marinum proliferation in zebrafish missing TNF-α.