IL-6 trans-signaling causes endothelial cell activation and barrier dysfunction in hantavirus infection

Hantaviruses are of major global health concern, causing over 150.000 infections annually.They cause two distinct acute inflammatory diseases, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Impaired endothelial barrier function is an important hallmark of both diseases, leading to vascular leakage and formation of oedema in major organs. What causes vascular leakage and determines the disease outcome remains unknown.Recent studies have identified IL-6 as a marker for disease severity and suggested an impact of IL-6 in hantavirus pathogenesis. IL-6 signaling occurs via the membrane-bound IL-6 receptor (IL-6R), known as classical signaling, or via the soluble IL-6R, known as transsignaling. As IL-6 trans-signaling has been shown to mediate mainly proinflammatory effects,we sought to investigate the role of IL-6 trans-signaling on vascular endothelial cells in hantavirus infection. In the present study, we examined the plasma concentration of sIL-6R in acute and convalescent Puumala virus (PUUV) infection. Further we examined IL-6 and CCL2 secretion, ICAM-1 and VE-cadherin expression and the barrier function upon IL-6 trans-signaling in PUUV infected endothelial cells. For the first time we showed increased levels of sIL-6R in acute HFRS and proved endothelial cell activation and barrier dysfunction upon PUUV infection and IL-6 trans-signaling. IL-6 and CCL2 secretion as well as ICAM-1 expression were increased, and VE-cadherin structures and barrier functions were disrupted.Our findings suggest an impact of IL-6 trans-signaling on vascular leakage and reveal new possible treatment targets for hantavirus infections