TY - JOUR T1 - Tyk2 as a target for immune regulation in human viral/bacterial pneumonia JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01953-2016 VL - 50 IS - 1 SP - 1601953 AU - Johanna Berg AU - Katja Zscheppang AU - Diana Fatykhova AU - Mario Tönnies AU - Torsten T. Bauer AU - Paul Schneider AU - Jens Neudecker AU - Jens C. Rückert AU - Stephan Eggeling AU - Maria Schimek AU - Achim D. Gruber AU - Norbert Suttorp AU - Stefan Hippenstiel AU - Andreas C. Hocke Y1 - 2017/07/01 UR - http://erj.ersjournals.com/content/50/1/1601953.abstract N2 - The severity and lethality of influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, the mechanisms in human lung tissue that provoke this increase in fatality are unknown and therapeutic immune modulatory options are lacking.We established a human lung ex vivo co-infection model to investigate innate immune related mechanisms contributing to the susceptibility of secondary pneumococcal pneumonia.We revealed that type I and III interferon (IFN) inhibits Streptococcus pneumoniae-induced interleukin (IL)-1β release. The lack of IL-1β resulted in the repression of bacterially induced granulocyte-macrophage colony-stimulating factor (GM-CSF) liberation. Specific inhibition of IFN receptor I and III-associated tyrosine kinase 2 (Tyk2) completely restored the S. pneumoniae-induced IL-1β–GM-CSF axis, leading to a reduction of bacterial growth. A preceding IAV infection of the human alveolus leads to a type I and III IFN-dependent blockade of the early cytokines IL-1β and GM-CSF, which are key for orchestrating an adequate innate immune response against bacteria. Their virally induced suppression may result in impaired bacterial clearance and alveolar repair.Pharmacological inhibition of Tyk2 might be a new treatment option to sustain beneficial endogenous GM-CSF levels in IAV-associated secondary bacterial pneumonia.Tyk2 inhibition might be a strategy to sustain endogenous GM-CSF levels in severe viral/bacterial pneumonia http://ow.ly/Owv130aWr6Z ER -