TBEV NS1 Induces Tissue-Specific Microvascular Endothelial Cell Permeability by Activating the TNF-α Signaling Pathway

<i>Orthoflavivirus encephalitidis</i> (tick-borne encephalitis virus, TBEV) is of high concern due to its ability to cause severe neurological manifestations. Despite the fact that the role of NS1 proteins from various mosquito-borne flaviviruses in pathogenesis and their ability to affect human endothelial permeability have been investigated, TBEV NS1 has thus far been insufficiently studied. In this study, human endothelial permeability was assessed using TEER and transwell permeability assays. Signaling pathways were determined by RNAseq. The ability of the NS1 protein of TBEV to affect human endothelial permeability was investigated for the first time. It was shown that recombinant TBEV NS1 produced in eucaryotic cells directly affected human lung microvascular endothelial cells (HLMVECs) in vitro but not human umbilical vein endothelial cells (HUVECs). It was indicated that TBEV NS1 induced endothelial hyperpermeability of HLMVECs through activating TNF-α and other inflammatory signaling pathways.