RT Journal Article
SR Electronic
T1 Tyk2 as a target for immune regulation in human viral/bacterial pneumonia
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1601953
DO 10.1183/13993003.01953-2016
VO 50
IS 1
A1 Johanna Berg
A1 Katja Zscheppang
A1 Diana Fatykhova
A1 Mario Tönnies
A1 Torsten T. Bauer
A1 Paul Schneider
A1 Jens Neudecker
A1 Jens C. Rückert
A1 Stephan Eggeling
A1 Maria Schimek
A1 Achim D. Gruber
A1 Norbert Suttorp
A1 Stefan Hippenstiel
A1 Andreas C. Hocke
YR 2017
UL http://erj.ersjournals.com/content/50/1/1601953.abstract
AB 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