Glucocorticoid Dysfunction in Children with Severe Malaria

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Jul 26

PMID 37492570

Authors

Leen Vandermosten

Fran Prenen

Balotin Fogang

Pauline Dagneau de Richecour

Sofie Knoops

Christiane Josiane Donkeu

Cathy Doric Piemba Nguefack

Jean-Voisin Taguebue

Paul Koki Ndombo

Bart Ghesquiere

Lawrence Ayong

Philippe E Van den Steen

Affiliations

Soon will be listed here.

Abstract

Introduction: Malaria 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 infection in mice. Here, GC responses were studied in Cameroon in children with uncomplicated malaria (UM), severe malaria (SM) and asymptomatic controls (AC).

Methods: To determine the sensitivity of leukocytes to GC signaling on a transcriptional level, we measured the 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.

Results: Total 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 stimulation with physiological levels of hydrocortisone. Interestingly, hydrocortisone induced increased levels of cAMP in AC, but not in clinical malaria patients.

Discussion: Altogether, 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.

Citing Articles

A systematic review and meta-analysis of cortisol levels in Plasmodium infections.

Kotepui K, Masangkay F, Wangdi K, Mahittikorn A, Majima H, Kotepui M Sci Rep. 2024; 14(1):18162.

PMID: 39107355 PMC: 11303744. DOI: 10.1038/s41598-024-68596-0.

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