de Oliveira Elaine Carvalho, Tibúrcio Rafael, Duarte Gabriela, Lago Amanda, de Melo Léon, Nunes Sara, Davanzo Gustavo Gastão, Martins Ana Júlia, Ribeiro Bruno Vinagre, Mothé Deborah, Menezes Juliana B P, Veras Patrícia, Tavares Natalia, Moraes-Vieira Pedro M, Brodskyn Cláudia Ida
Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.
University of California San Francisco, Department of Medicine, San Francisco, California, United States.
PLoS Negl Trop Dis. 2025 Jan 7;19(1):e0012763. doi: 10.1371/journal.pntd.0012763. eCollection 2025 Jan.
Macrophages represent a fundamental component of the innate immune system that play a critical role in detecting and responding to pathogens as well as danger signals. Leishmania spp. infections lead to a notable alteration in macrophage metabolism, whereby infected cells display heightened energy metabolism that is linked to the integrity of host mitochondria. However, little is known about how different species of Leishmania manipulate host metabolism. Here, we demonstrate that despite differences in their mechanisms for evading host immune responses, L. amazonensis and L. braziliensis induce comparable disruptions in key metabolic pathways. We found that infected macrophages exhibited an overall elevation in energy metabolism regardless of the parasite strain, evidenced by the elevation in glycolysis and oxygen consumption rates, along with increased proton leak and decreased ATP production. We also analyzed the effects of both Leishmania spp. strain infection on mitochondria function, further revealing that infected cells display heightened mitochondrial mass and membrane potential. To investigate the metabolic pathways required for Leishmania amastigotes to persist in BMDMs, we pre-treated cells with small molecule drugs that target major metabolic pathways, revealing that perturbations in several metabolic processes affected parasite survival in a strain-independent manner. Treatments with inhibitors of the oxidative phosphorylation and glycolysis substantially reduced parasite loads. Collectively, our findings suggest that L.amazonensis and L.braziliensis exploit host cell metabolic pathways similarly to survive in macrophages.
巨噬细胞是固有免疫系统的基本组成部分，在检测病原体和危险信号并做出反应方面发挥着关键作用。利什曼原虫属感染会导致巨噬细胞代谢发生显著改变，受感染的细胞表现出能量代谢增强，这与宿主线粒体的完整性有关。然而，对于不同种类的利什曼原虫如何操纵宿主代谢，我们知之甚少。在此，我们证明，尽管亚马逊利什曼原虫和巴西利什曼原虫逃避宿主免疫反应的机制存在差异，但它们在关键代谢途径中引起的破坏具有可比性。我们发现，无论寄生虫菌株如何，受感染的巨噬细胞的能量代谢总体上都会升高，糖酵解和耗氧率升高、质子泄漏增加以及ATP生成减少都证明了这一点。我们还分析了两种利什曼原虫菌株感染对线粒体功能的影响，进一步揭示受感染的细胞表现出线粒体质量增加和膜电位升高。为了研究利什曼原虫无鞭毛体在骨髓来源的巨噬细胞（BMDMs）中存活所需的代谢途径，我们用靶向主要代谢途径的小分子药物对细胞进行预处理，结果表明几个代谢过程的扰动以菌株独立的方式影响寄生虫的存活。用氧化磷酸化和糖酵解抑制剂进行处理可显著降低寄生虫载量。总的来说，我们的研究结果表明，亚马逊利什曼原虫和巴西利什曼原虫以类似的方式利用宿主细胞代谢途径在巨噬细胞中存活。
