Yellow fever virus infection triggers proinflammatory and prothrombotic responses in endothelial cells through NF-κB and MAPK signaling pathways.

Yellow fever (YF), caused by the Yellow Fever Virus (YFV), is a disease endemic in South America and Africa with clinical manifestations ranging from fever to fatal organ failure and hemorrhagic complications. The role of the endothelium in the pathogenesis of YFV is not completely understood. To investigate the effects of YFV infection on human endothelial cells (EC), human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC-1) were infected with the YFV 17DD strain. Viral infection, cell death, cell adhesion, adhesion molecules, cytokines, von Willebrand factor (VWF), nitric oxide (NO), tissue factor (TF), interferon-I, clotting time and signaling pathways were analyzed by plaque assays, immunofluorescence, cytometry, ELISA, RT-qPCR, DAF-FM DA probe, Griess reaction and Western blot. The results showed that HUVEC and HMEC-1 were susceptible to YFV infection according to virus titer and presence of intracellular dsRNA, which induced an increase in apoptosis at 3- and 7-days post-infection (pi), respectively. At earlier time points (4-48 h pi), infected EC exhibited upregulation of E-selectin and ICAM-1, secretion of IL-1β, IL-6 and VWF, decreased eNOS mRNA, NO production, clotting time, and increased TF and interferon-I mRNA levels, as well as increased adhesion of platelets and leukocytes to EC. Mechanistically, YFV infection led to activation of the NF-κB and MAPK signaling pathways. We conclude that YFV infection triggers a proinflammatory and prothrombotic response in EC that likely contributes to the vascular dysfunction and hemorrhagic manifestations observed in YF. These findings point to potential targets for therapeutic intervention.