Program in Biology, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
Department of Biology, New York University, New York, NY, USA.
Nat Metab. 2021 Jul;3(7):1001-1016. doi: 10.1038/s42255-021-00404-9. Epub 2021 Jun 10.
Host responses to infection with the malaria parasite Plasmodium falciparum vary among individuals for reasons that are poorly understood. Here we reveal metabolic perturbations as a consequence of malaria infection in children and identify an immunosuppressive role of endogenous steroid production in the context of P. falciparum infection. We perform metabolomics on matched samples from children from two ethnic groups in West Africa, before and after infection with seasonal malaria. Analysing 306 global metabolomes, we identify 92 parasitaemia-associated metabolites with impact on the host adaptive immune response. Integrative metabolomic and transcriptomic analyses, and causal mediation and moderation analyses, reveal an infection-driven immunosuppressive role of parasitaemia-associated pregnenolone steroids on lymphocyte function and the expression of key immunoregulatory lymphocyte genes in the Gouin ethnic group. In children from the less malaria-susceptible Fulani ethnic group, we observe opposing responses following infection, consistent with the immunosuppressive role of endogenous steroids in malaria. These findings advance our understanding of P. falciparum pathogenesis in humans and identify potential new targets for antimalarial therapeutic interventions.
宿主对疟原虫恶性疟原虫感染的反应因人而异，其原因尚不清楚。在这里，我们揭示了疟疾感染儿童的代谢紊乱，并确定了内源性类固醇产生在恶性疟原虫感染背景下的免疫抑制作用。我们对来自西非两个民族的儿童在季节性疟疾感染前后的匹配样本进行了代谢组学分析。分析了 306 个全球代谢组，我们确定了 92 个与寄生虫血症相关的代谢物，这些代谢物对宿主适应性免疫反应有影响。综合代谢组学和转录组学分析，以及因果中介和调节分析，揭示了寄生虫血症相关孕烯醇酮类固醇在 Gouin 民族的淋巴细胞功能和关键免疫调节淋巴细胞基因表达方面的感染驱动的免疫抑制作用。在来自不易感染疟疾的富拉尼民族的儿童中，我们观察到感染后的相反反应，这与内源性类固醇在疟疾中的免疫抑制作用一致。这些发现增进了我们对人类恶性疟原虫发病机制的理解，并确定了抗疟治疗干预的潜在新靶点。
