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    Tyk2 as a Target for Immune Regulation in Human Viral/Bacterial Pneumonia (2017)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Berg, Johanna
    Zscheppang, Katja
    Fatykhova, Diana
    Tönnies, Mario
    Bauer, Torsten T
    Schneider, Paul
    Neudecker, Jens
    Rückert, Jens C
    Eggeling, Stephan
    Schimek, Maria
    Gruber, Achim D (WE 12)
    Suttorp, Norbert
    Hippenstiel, Stefan
    Hocke, Andreas C
    Quelle
    The European respiratory journal; 50(1) — S. AR 1601953
    ISSN: 0903-1936
    Sprache
    Englisch
    Verweise
    DOI: 10.1183/13993003.01953-2016
    Pubmed: 28705941
    Kontakt
    Institut für Tierpathologie

    Robert-von-Ostertag-Str. 15
    Gebäude 12
    14163 Berlin
    +49 30 838 62450

    Abstract / Zusammenfassung

    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.