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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<sub>reg</sub>) which depend on PI3K&delta; for suppressive functioning</p> <p>2)&nbsp;&nbsp;&nbsp; Viral and T<sub>reg</sub> 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<sub>reg</sub> 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>


06 Dec 2016

Grant details
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
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