| First Author | Osada-Oka M | Year | 2019 |
| Journal | Int Immunol | Volume | 31 |
| Issue | 12 | Pages | 781-793 |
| PubMed ID | 31201418 | Mgi Jnum | J:282307 |
| Mgi Id | MGI:6378667 | Doi | 10.1093/intimm/dxz048 |
| Citation | Osada-Oka M, et al. (2019) Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection. Int Immunol 31(12):781-793 |
| abstractText | Macrophages are major components of tuberculosis (TB) granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis. We herein showed the strong expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in TB granulomas and more rapid death of HIF-1alpha-conditional knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although interferon-gamma (IFN-gamma) is a critical host-protective cytokine against intracellular pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even after activation with IFN-gamma. These results prompted us to investigate the role of HIF-1alpha in host defenses against infection. We found that the expression of lactate dehydrogenase-A (LDH-A) was controlled by HIF-1alpha in M. tuberculosis-infected macrophages IFN-gamma independently. LDH-A is an enzyme that converts pyruvate to lactate and we found that the intracellular level of pyruvate in HIF-1alpha-deficient bone marrow-derived macrophages (BMDMs) was significantly higher than in WT BMDMs. Intracellular bacillus replication was enhanced by an increase in intracellular pyruvate concentrations, which were decreased by LDH-A. Mycobacteria in phagosomes took up exogenous pyruvate more efficiently than glucose, and used it as the feasible carbon source for intracellular growth. These results demonstrate that HIF-1alpha prevents the hijacking of pyruvate in macrophages, making it a fundamental host-protective mechanism against M. tuberculosis. |
