Tyk2 as a target for immune regulation in human viral/bacterial pneumonia.

Abstract

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.

• Authors: Johanna Berg, Katja Zscheppang, Diana Fatykhova, Mario Tönnies, Torsten T Bauer, Paul Schneider, Jens Neudecker, Jens C Rückert, Stephan Eggeling, Maria Schimek, Achim D Gruber, Norbert Suttorp, Stefan Hippenstiel, Andreas C Hocke
• Journal: The European respiratory journal (Eur Respir J) Vol. 50 Issue 1 (07 2017) ISSN: 1399-3003 [Electronic] England
• PMID: 28705941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©ERS 2017.

Chemical References

• IL1B protein, human
• Immunologic Factors
• Interleukin-1beta
• Granulocyte-Macrophage Colony-Stimulating Factor
• Interferons
• TYK2 Kinase
• TYK2 protein, human

Topics

• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Humans
• Immunity, Innate (drug effects)
• Immunologic Factors
• Influenza A virus
• Influenza, Human (drug therapy, immunology)
• Interferons (pharmacology)
• Interleukin-1beta (metabolism)
• Lung (drug effects)
• Pneumonia, Bacterial (drug therapy, immunology)
• Staphylococcal Infections (drug therapy, immunology)
• TYK2 Kinase (antagonists & inhibitors, metabolism)