Glucocorticoid dysfunction in children with severe malaria

Frontiers in Immunology

Immunology

Pauline Dagneau de Richecour¹  Philippe E. Van den Steen¹  Sofie Knoops¹  Fran Prenen¹  Leen Vandermosten¹  Christiane Josiane Donkeu²  Lawrence Ayong²  Balotin Fogang²  Bart Ghesquière³  Cathy Doric Piemba Nguefack⁴  Jean-Voisin Taguebue⁴  Paul Koki Ndombo⁴ 

[1] Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium;Malaria Research Unit, Centre Pasteur du Cameroun, Yaoundé, Cameroon;Metabolomics Expertise Center, Center for Cancer Biology, VIB Center for Cancer Biology, Leuven, Belgium;Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium;Mother and Child Center, Chantal Biya Foundation, Yaoundé, Cameroon;

关键词: malaria;    glucocorticoids;    plasmodium;    metabolomics;    cortisol;   

DOI  :  10.3389/fimmu.2023.1187196

 received in 2023-03-15, accepted in 2023-06-23,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionMalaria remains a widespread health problem with a huge burden. Severe or complicated malaria is highly lethal and encompasses a variety of pathological processes, including immune activation, inflammation, and dysmetabolism. Previously, we showed that adrenal hormones, in particular glucocorticoids (GCs), play critical roles to maintain disease tolerance during Plasmodium infection in mice. Here, GC responses were studied in Cameroon in children with uncomplicated malaria (UM), severe malaria (SM) and asymptomatic controls (AC).MethodsTo determine the sensitivity of leukocytes to GC signaling on a transcriptional level, we measured the ex vivo induction of glucocorticoid induced leucine zipper (GILZ) and FK506-binding protein 5 (FKBP5) by GCs in human and murine leukocytes. Targeted tracer metabolomics on peripheral blood mononuclear cells (PBMCs) was performed to detect metabolic changes induced by GCs. ResultsTotal cortisol levels increased in patients with clinical malaria compared to AC and were higher in the SM versus UM group, while cortisol binding globulin levels were unchanged and adrenocorticotropic hormone (ACTH) levels were heterogeneous. Induction of both GILZ and FKBP5 by GCs was significantly reduced in patients with clinical malaria compared to AC and in malaria-infected mice compared to uninfected controls. Increased activity in the pentose phosphate pathway was found in the patients, but this was not affected by ex vivo stimulation with physiological levels of hydrocortisone. Interestingly, hydrocortisone induced increased levels of cAMP in AC, but not in clinical malaria patients. DiscussionAltogether, this study shows that patients with SM have increased cortisol levels, but also a decreased sensitivity to GCs, which may clearly contribute to the severity of disease.

【 授权许可】

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Copyright © 2023 Vandermosten, Prenen, Fogang, Dagneau de Richecour, Knoops, Donkeu, Nguefack, Taguebue, Ndombo, Ghesquière, Ayong and Van den Steen