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. </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 (PI3Kδ), and that inhibition PI3Kδ will be protective via the following mechanisms.</p> <p>1) Influenza-induced expansion of immunosuppressive regulatory T-cells (T<sub>reg</sub>) which depend on PI3Kδ for suppressive functioning</p> <p>2) Viral and T<sub>reg</sub> mediated suppression of neutrophil function</p> <p>3) 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> </p> <p>The goals are:</p> <p>1) To determin whether PI3Kδ-null animals are resistant to secondary streptococcal pneumonia.</p> <p>2) To use tools including T<sub>reg</sub> depleted animals, conditional knockout animals and small molecule PI3Kδ 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. </p>
£516,560 06 Dec 2016
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Amount Awarded | 516560 |
Applicant Surname | Conway Morris |
Approval Committee | Clinical Interview Committee |
Award Date | 2016-12-06T00:00:00+00:00 |
Financial Year | 2016/17 |
Grant Programme: Title | Clinical Research Career Development Fellowship |
Internal ID | 205214/Z/16/Z |
Lead Applicant | Dr Andrew Conway Morris |
Planned Dates: End Date | 2020-09-01T00:00:00+00:00 |
Planned Dates: Start Date | 2017-09-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |
Sponsor(s) | Prof Edwin Chilvers |