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Adrenal hormones mediate disease tolerance in malaria

Journal Contribution - Journal Article

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.

Journal: Nat Commun
ISSN: 2041-1723
Issue: 1
Volume: 9
Pages: 4525
Publication year:2018
Keywords:Adrenal Glands/immunology, Adrenalectomy, Animals, Blood Glucose/drug effects, Brain/drug effects, Corticosterone/immunology, Cytokines/drug effects, Dexamethasone/pharmacology, Disease Models, Animal, Epinephrine/immunology, Glucocorticoids/immunology, Glycogen/metabolism, Hormones/immunology, Hydrocortisone/immunology, Hypoglycemia/immunology, Inflammation, Liver/drug effects, Lung/drug effects, Malaria/immunology, Mice, Mineralocorticoids/immunology, Norepinephrine/immunology, Plasmodium berghei, Plasmodium chabaudi, Survival Rate