JAK/STAT inhibition restores disease tolerance in malaria-infected glucocorticoid receptor knockout mice.

Disease tolerance is a defense strategy, whereby the host limits tissue damage, without affecting the pathogen load. In malaria, the disease tolerance mechanisms by which many infected individuals are protected against severe disease, are still incompletely understood. In this study, we show that endogenous glucocorticoids are integral components of disease tolerance in malaria, as genetic deletion of the glucocorticoid receptor in mice resulted in the development of lethal hypoglycemia during Plasmodium chabaudi AS infection. This was paralleled by altered metabolism in liver and spleen, marked by increased glucose uptake, a predominant glycolytic transcriptome, reduced gluconeogenic gene expression and depletion of glycogen stores. Hypoglycemia was highly associated with activation of the JAK/STAT pathway in the liver and spleen. Treatment with ruxolitinib, a JAK1/2 inhibitor, ensured survival by protecting against lethal hypoglycemia. These findings highlight the pivotal role of endogenous glucocorticoids in disease tolerance, and suggest a potential therapeutic role for ruxolitinib in managing malaria-induced hypoglycemia.