Tick-borne flavivirus NS5 antagonizes interferon signaling by inhibiting the catalytic activity of TYK2.

The mechanisms utilized by different flaviviruses to evade antiviral functions of interferons are varied and incompletely understood. Using virological approaches, biochemical assays, and mass spectrometry analyses, we report here that the NS5 protein of tick-borne encephalitis virus (TBEV) and Louping Ill virus (LIV), two related tick-borne flaviviruses, antagonize JAK-STAT signaling through interactions with the tyrosine kinase 2 (TYK2). Co-immunoprecipitation (co-IP) experiments, yeast gap-repair assays, computational protein-protein docking and functional studies identify a stretch of 10 residues of the RNA dependent RNA polymerase domain of tick-borne flavivirus NS5, but not mosquito-borne NS5, that is critical for interactions with the TYK2 kinase domain. Additional co-IP assays performed with several TYK2 orthologs reveal that the interaction is conserved across mammalian species. In vitro kinase assays show that TBEV and LIV NS5 reduce the catalytic activity of TYK2. Our results thus illustrate a novel mechanism by which viruses suppress the interferon response.

Pulmonary vasculitis mimicking chronic thromboembolic disease.

A 29-year-old female patient presented with chest pain, breathlessness and syncope on the background of constitutional symptoms, oral ulceration and a rash. Multiple investigations were performed, including a CT pulmonary angiogram (CTPA) that was initially felt to show imaging features consistent with a diagnosis of chronic thromboembolic disease (CTED). The patient was referred to a tertiary pulmonary hypertension centre and the possibility of pulmonary vasculitis was raised. Subsequent positron emission tomography (PET)-CT revealed imaging features supporting this diagnosis. The patient was treated with intravenous cyclophosphamide infusions, following which her symptoms improved. A repeat PET-CT 6 months after treatment showed resolution in pulmonary artery and mediastinal uptake, but persistence of pulmonary artery occlusions on a repeat CTPA. A final diagnosis of pulmonary vasculitis secondary to Behçet's disease was made. This case report aims to raise awareness of the imaging features of CTED and its mimics.