Prenen Fran, Vandermosten Leen, Knoops Sofie, Pollenus Emilie, Possemiers Hendrik, Dagneau de Richecour Pauline, Caratti Giorgio, Cawthorne Christopher, Vettorazzi Sabine, Cranshoff Yevva, Schols Dominique, Claes Sandra, Deroose Christophe M, Himmelreich Uwe, Tuckermann Jan, Van den Steen Philippe E
Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, 3000, Belgium.
Institute of Molecular Endocrinology and Physiology, German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm University, Ulm, 89081, Germany.
EMBO Mol Med. 2025 Jul 23. doi: 10.1038/s44321-025-00264-w.
Disease tolerance is a key defense mechanism that limits damage to the host without directly reducing pathogen levels. In malaria, these mechanisms are essential for preventing severe disease and death but remain poorly understood. In this study, we show that glucocorticoid receptor (GR)-mediated processes play a vital role in disease tolerance during Plasmodium chabaudi AS infection. GR deletion in infected mice resulted in lethal hypoglycemia and a cytokine storm. Hypoglycemia was driven by severe metabolic dysfunction in the liver and spleen, characterized by increased glucose uptake, glycogen depletion, a dominant glycolytic profile and reduced gluconeogenic gene expression. Importantly, this hypoglycemic state was strongly associated with overactivation of the JAK/STAT pathway and excessive cytokine expression. Treatment with the JAK1/2 inhibitor ruxolitinib significantly improved survival by preventing lethal hypoglycemia and suppressing hyperinflammation. Our findings reveal a novel link between GR signaling, STAT3 activation, cytokine expression and glucose metabolism during severe malaria. This underscores the critical role of GR-mediated processes in disease tolerance and highlights ruxolitinib as a promising adjuvant therapy for managing life-threatening metabolic complications in malaria.
疾病耐受性是一种关键的防御机制，可在不直接降低病原体水平的情况下限制对宿主的损害。在疟疾中，这些机制对于预防严重疾病和死亡至关重要，但仍知之甚少。在本研究中，我们表明糖皮质激素受体（GR）介导的过程在感染查巴迪疟原虫AS期间的疾病耐受性中起着至关重要的作用。感染小鼠中GR的缺失导致致命性低血糖和细胞因子风暴。低血糖是由肝脏和脾脏严重的代谢功能障碍驱动的，其特征是葡萄糖摄取增加、糖原耗竭、糖酵解占主导地位以及糖异生基因表达降低。重要的是，这种低血糖状态与JAK/STAT途径的过度激活和细胞因子的过度表达密切相关。用JAK1/2抑制剂鲁索替尼治疗可通过预防致命性低血糖和抑制过度炎症反应显著提高生存率。我们的研究结果揭示了严重疟疾期间GR信号传导、STAT3激活、细胞因子表达和葡萄糖代谢之间的新联系。这强调了GR介导的过程在疾病耐受性中的关键作用，并突出了鲁索替尼作为治疗疟疾中危及生命的代谢并发症的一种有前景的辅助疗法。
