Interferons Suppress Il-1 beta Dependent Gm-Csf In Post-Influenza Pneumococcal Infection Of Human Lungs

Pneumologie(2016)

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Abstract
The severity and lethality in influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, mechanisms in human lung tissue provoking this increase in fatality are unknown. 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 observed induction of type I, II, and III interferons (IFN) in alveolar epithelial type II cells (AEC II) after IAV infection and revealed their inhibitory effect on Streptococcus pneumoniae (S. pneumoniae) induced IL-1β release by alveolar macrophages (AM). In contrast, other cytokines such as IL-6, IL-8, IL-10, or TNFα remained unaffected. However, the lack of AM derived IL-1β resulted in suppression of S. pneumoniae induced granulocyte-macrophage colony stimulating factor (GM-CSF) liberation in AEC II. The results further suggested that IFN suppressed GM-CSF by two mechanisms. First, via indirect inhibition of the AM-IL-1β axis and, second, by directly affecting GM-CSF induction in AEC II. We conclude that a preceding IAV infection of the human alveolus leads to an IFN dependent modulation of the early cytokines IL-1β and GM-CSF which play a key role for orchestrating an adequate innate immune response against S. pneumoniae. Their suppression may result in impaired bacterial clearance and alveolar repair. The use of human lung tissue to study viral/bacterial co-infections displayed strategic differences in the regulation of these key cytokines when compared to mice. This observation appears of particular importance as GM-CSF is considered for immune modulatory treatment in acute lung injury.
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Key words
pneumococcal infection,human lungs,gm-csf,post-influenza
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