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-1α (HIF-1α) in TB granulomas and more rapid death of HIF-1α-conditional knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although interferon-γ (IFN-γ) is a critical host-protective cytokine against intracellular pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even after activation with IFN-γ. These results prompted us to investigate the role of HIF-1α in host defenses against infection. We found that the expression of lactate dehydrogenase-A (LDH-A) was controlled by HIF-1α in M. tuberculosis-infected macrophages IFN-γ independently. LDH-A is an enzyme that converts pyruvate to lactate and we found that the intracellular level of pyruvate in HIF-1α-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-1α prevents the hijacking of pyruvate in macrophages, making it a fundamental host-protective mechanism against M. tuberculosis.

中文翻译：

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代谢对糖酵解的适应是巨噬细胞对结核分枝杆菌感染的基本防御机制。

巨噬细胞是结核（TB）肉芽肿的主要成分，负责抵抗细胞内病原体结核分枝杆菌的宿主防御。我们在本文中显示，在结核分枝杆菌感染后，低氧诱导因子-1α（HIF-1α）在结核性肉芽肿中表达强，而HIF-1α条件性剔除小鼠比野生型（WT）小鼠死亡更快。尽管干扰素-γ（IFN-γ）是抵抗细胞内病原体的关键宿主保护细胞因子，但即使缺乏IFN-γ的激活，HIF-1缺陷型巨噬细胞仍能使结核分枝杆菌生长。这些结果促使我们研究HIF-1α在宿主抵抗感染中的作用。我们发现乳酸脱氢酶-A（LDH-A）的表达受结核分枝杆菌感染的巨噬细胞IFN-γ中HIF-1α的独立控制。LDH-A是一种将丙酮酸转化为乳酸的酶，我们发现在HIF-1α缺乏的骨髓巨噬细胞（BMDM）中，丙酮酸的细胞内水平显着高于野生型BMDM。细胞内丙酮酸浓度的增加增强了细胞内芽孢杆菌的复制，而LDH-A降低了细胞内丙酮酸的浓度。吞噬体中的分枝杆菌比葡萄糖更有效地吸收外源丙酮酸，并将其用作细胞内生长的可行碳源。这些结果证明，HIF-1α防止巨噬细胞中丙酮酸的劫持，使其成为抵抗结核分枝杆菌的基本宿主保护机制。细胞内丙酮酸浓度的增加增强了细胞内芽孢杆菌的复制，而LDH-A降低了细胞内丙酮酸的浓度。吞噬体中的分枝杆菌比葡萄糖更有效地吸收外源丙酮酸，并将其用作细胞内生长的可行碳源。这些结果证明，HIF-1α防止巨噬细胞中丙酮酸的劫持，使其成为抵抗结核分枝杆菌的基本宿主保护机制。细胞内丙酮酸浓度的增加增强了细胞内芽孢杆菌的复制，而LDH-A降低了细胞内丙酮酸的浓度。吞噬体中的分枝杆菌比葡萄糖更有效地吸收外源丙酮酸，并将其用作细胞内生长的可行碳源。这些结果证明，HIF-1α防止巨噬细胞中丙酮酸的劫持，使其成为抵抗结核分枝杆菌的基本宿主保护机制。