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

<p>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.&nbsp;</p> <p>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 (PI3K&delta;), and that inhibition PI3K&delta; will be protective via the following mechanisms.</p> <p>1)&nbsp;&nbsp;&nbsp; Influenza-induced expansion of immunosuppressive regulatory T-cells (T_reg) which depend on PI3K&delta; for suppressive functioning</p> <p>2)&nbsp;&nbsp;&nbsp; Viral and T_reg mediated suppression of neutrophil function</p> <p>3)&nbsp;&nbsp;&nbsp; A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by <em>Streptococcus pneumoniae</em>.</p> <p>&nbsp;</p> <p>The goals are:</p> <p>1) To determin whether PI3K&delta;-null animals are resistant to secondary streptococcal pneumonia.</p> <p>2) To use tools including T_reg depleted animals, conditional knockout animals and small molecule PI3K&delta; inhibitors to explore mechanisms of resistance.</p> <p>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.</p> <p>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.&nbsp;</p>

£516,560

06 Dec 2016