Pathogenesis and therapy of the macrophage activation syndrome in virus-induced mouse models.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, hyperinflammatory disease, characterized by an overwhelming cytokine storm and systemic overactivation of immune cells, causing high morbidity and often mortality in children and adults. Two subtypes can be distinguished, primary ‘genetic’ HLH and secondary ‘acquired’ HLH. In contrast to primary HLH, the pathogenesis of secondary HLH remains incompletely understood. Specifically the remarkable association between viral infections and the onset of HLH requires further investigation. Herpesviruses are considered the predominant triggers of active HLH episodes. Therefore, this projects aims to develop a new mouse model of virus-associated secondary HLH using mouse herpesviruses, such as mouse cytomegalovirus. In this new model, HLH-like symptoms and excessive immune activation will be thoroughly characterized. After validation of the model, possible pathologic pathways will be studied to decipher the contributions of viral replication, different immune cells and pro-inflammatory cytokines to HLH pathogenesis, in order to devise novel, targeted therapies that could be translated to the patient.