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Tyk2 as a target for immune regulation in human viral/bacterial pneumonia #MMPMID28705941
Berg J; Zscheppang K; Fatykhova D; Tonnies M; Bauer TT; Schneider P; Neudecker J; Ruckert JC; Eggeling S; Schimek M; Gruber AD; Suttorp N; Hippenstiel S; Hocke AC
Eur Respir J 2017[Jul]; 50 (1): ä PMID28705941show ga
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)-1beta release. The lack of IL-1beta 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-1beta-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-1beta 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.
Eur+Respir+J 2017 ; 50 (1): ä
