Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, VIC, 3010, Australia.
Immunol Cell Biol. 2020 Nov;98(10):832-844. doi: 10.1111/imcb.12394. Epub 2020 Sep 8.
Leishmania are parasitic protists that cause a spectrum of diseases in humans characterized by the formation of granulomatous lesions in the skin or other tissues, such as liver and spleen. The extent to which Leishmania granulomas constrain or promote parasite growth is critically dependent on the host T-helper type 1/T-helper type 2 immune response and the localized functional polarization of infected and noninfected macrophages toward a classically (M1) or alternatively (M2) activated phenotype. Recent studies have shown that metabolic reprograming of M1 and M2 macrophages underpins the capacity of these cells to act as permissive or nonpermissive host reservoirs, respectively. In this review, we highlight the metabolic requirements of Leishmania amastigotes and the evidence that these parasites induce and/or exploit metabolic reprogramming of macrophage metabolism. We also focus on recent studies highlighting the role of key macrophage metabolic signaling pathways, such as mechanistic target of rapamycin, adenosine monophosphate-activated protein kinase and peroxisome proliferator receptor gamma in regulating the pathological progression of Leishmania granulomas. These studies highlight the intimate connectivity between Leishmania and host cell metabolism, the need to investigate these interactions in vivo and the potential to exploit host cell metabolic signaling pathways in developing new host-directed therapies.
利什曼原虫是一种寄生的原生动物，可引起人类一系列疾病，其特征是在皮肤或其他组织（如肝脏和脾脏）中形成肉芽肿性病变。利什曼原虫肉芽肿限制或促进寄生虫生长的程度，极大地取决于宿主辅助性 T 细胞 1/辅助性 T 细胞 2 免疫反应以及感染和未感染的巨噬细胞向经典（M1）或替代性（M2）激活表型的局部功能极化。最近的研究表明，M1 和 M2 巨噬细胞的代谢重编程是这些细胞分别作为允许或非允许宿主储库的能力的基础。在这篇综述中，我们强调了利什曼无鞭毛体的代谢需求以及这些寄生虫诱导和/或利用巨噬细胞代谢代谢重编程的证据。我们还重点介绍了最近的研究，这些研究强调了关键巨噬细胞代谢信号通路的作用，如雷帕霉素靶蛋白、单磷酸腺苷激活蛋白激酶和过氧化物酶体增殖物激活受体 γ 在调节利什曼原虫肉芽肿的病理进展中的作用。这些研究强调了利什曼原虫和宿主细胞代谢之间的密切联系，需要在体内研究这些相互作用，并有可能利用宿主细胞代谢信号通路开发新的宿主定向治疗方法。
