Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Africa Health Research Institute, University of KwaZulu Natal, Durban, South Africa.
Nat Commun. 2023 Sep 6;14(1):5472. doi: 10.1038/s41467-023-40545-x.
Mycobacterium tuberculosis (Mtb) disrupts glycolytic flux in infected myeloid cells through an unclear mechanism. Flux through the glycolytic pathway in myeloid cells is inextricably linked to the availability of NAD, which is maintained by NAD salvage and lactate metabolism. Using lung tissue from tuberculosis (TB) patients and myeloid deficient LDHA (Ldha) mice, we demonstrate that glycolysis in myeloid cells is essential for protective immunity in TB. Glycolytic myeloid cells are essential for the early recruitment of multiple classes of immune cells and IFNγ-mediated protection. We identify NAD depletion as central to the glycolytic inhibition caused by Mtb. Lastly, we show that the NAD precursor nicotinamide exerts a host-dependent, antimycobacterial effect, and that nicotinamide prophylaxis and treatment reduce Mtb lung burden in mice. These findings provide insight into how Mtb alters host metabolism through perturbation of NAD(H) homeostasis and reprogramming of glycolysis, highlighting this pathway as a potential therapeutic target.
结核分枝杆菌（Mtb）通过一种不明机制破坏感染的髓样细胞中的糖酵解通量。髓样细胞中糖酵解途径的通量与 NAD 的可用性密切相关，而 NAD 的可用性由 NAD 回收和乳酸代谢维持。利用结核病（TB）患者的肺组织和髓样细胞缺失 LDHA（Ldha）的小鼠，我们证明髓样细胞中的糖酵解对 TB 的保护性免疫至关重要。糖酵解性髓样细胞对于多种免疫细胞的早期募集和 IFNγ介导的保护作用是必需的。我们确定 NAD 耗竭是 Mtb 引起的糖酵解抑制的核心。最后，我们表明 NAD 前体烟酰胺发挥宿主依赖性、抗分枝杆菌作用，烟酰胺预防和治疗可减少小鼠肺部的 Mtb 负担。这些发现深入了解了 Mtb 如何通过干扰 NAD（H）动态平衡和糖酵解重编程来改变宿主代谢，突出了该途径作为一种潜在的治疗靶点。
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