Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia (360G-Wellcome-205214_Z_16_Z)

Secondary pneumonia following influenza infection is common, with considerable associated morbidity and mortality. Strikingly, secondary infections tend to arise from bacteria which live otherwise asymptomatically in the oropharynx. Based on existing data, I hypothesise that the development of secondary streptococcal pneumonia is dependent on a key immune-cell molecular pathway, namely Phosphoinsitol-3-Kinase delta (PI3Kδ), and that inhibition PI3Kδ will be protective via the following mechanisms. 1) Influenza-induced expansion of immunosuppressive regulatory T-cells (Treg) which depend on PI3Kδ for suppressive functioning 2) Viral and Treg mediated suppression of neutrophil function 3) A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by Streptococcus pneumoniae. The goals are: 1) To determin whether PI3Kδ-null animals are resistant to secondary streptococcal pneumonia. 2) To use tools including Treg depleted animals, conditional knockout animals and small molecule PI3Kδ inhibitors to explore mechanisms of resistance. 3) To develop a more clinically relevant murine model secondary pneumonia, using a streptococcal colonisation model which when exposed to influenza will develop secondary pneumonia. 4) To characterise the respiratory microbiome of animals at various stages will be characterised, looking for factors that may facilitate or militate against development of secondary pneumonia.