MALARIA PARASITES IN COMBINATION WITH INTERFERON-Γ INDUCE GLUCOCORTICOID RESISTANCE IN PULMONARY ENDOTHELIUM

Due to their anti-inflammatory properties endogenous glucocorticoids (GCs) contribute to the control of the immune system. Exogenous GCs are used as anti-inflammatory therapeutics in patients suffering from a broad spectrum of inflammatory diseases. However, treatment failure due to GC resistance is frequently reported. Preliminary data show prominent GC resistance in a model of malaria-associated acute respiratory distress syndrome (MA-ARDS). MA-ARDS causes
considerable suffering in patients, often results in death and is characterized by pulmonary edema and abundant inflammatory infiltrates consisting mainly of monocytes and lymphocytes. My project contains four aims: (i) defining the regulation of GC sensitivity in endothelial cells, (ii) defining the regulation of GC sensitivity in leukocytes in MA-ARDS, (iii) obtaining a genome-wide view of the effects of GC resistance in both endothelial cells and leukocytes and (iv) discovery of
the biochemical and cellular mechanisms of this resistance. State-of-the-art technologies will be used, including new GC-resistant and GC-sensitive mouse models of MA-ARDS, in vitro and ex vivo
GC sensitivity tests, genome-wide approaches (RNA-Seq and ChIP-Seq) and specific biochemical assays. Therefore, this project will uncover a new layer in the endogenous regulation of
inflammation. We also believe that these new insights will be instrumental for the design of novel therapies aiming at the restoration of GC sensitivity.