Adrenal hormones mediate disease tolerance in malaria


P Van den Steen3; L Vandermosten3; T T Pham3; S Knoops13; C De Geest3; N Lays3; K Van der Molen3; C J Kenyon1; M Verma1; K E Chapman1; F Schuit2; K De Bosscher4; G Opdenakker3
1 Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, UK;  2 Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Belgium;  3 Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Belgium;  4 Receptor Research Laboratories, Nuclear Receptor Lab, VIB Center for Medical Biotechnology, Ghent University, Belgium


Malaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early death, independently of parasitemia. Surprisingly, adrenalectomy differentially affects malaria-induced inflammation by increasing circulating cytokines and inflammation in the brain but not in the liver or lung. Furthermore, without affecting the transcription of hepatic gluconeogenic enzymes, adrenalectomy causes exhaustion of hepatic glycogen and insulin-independent lethal hypoglycemia upon infection. This hypoglycemia is not prevented by glucose administration or TNF-α neutralization. In contrast, treatment with a synthetic glucocorticoid (dexamethasone) prevents the hypoglycemia, lowers cerebral cytokine expression and increases survival rates. Overall, we conclude that in malaria, adrenal hormones do not protect against lung and liver inflammation. Instead, they prevent excessive systemic and brain inflammation and severe hypoglycemia, thereby contributing to tolerance. Ref.: Vandermosten et al., Nat Commun. 2018 Oct 30;9(1):4525. doi: 10.1038/s41467-018-06986-5.

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