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Title: The innate immune rheostat : miRNA and negative regulation pathways which determine susceptibility to secondary bacterial complication
Author: Godlee, Alexandra Elisabeth Clare
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Analysis of post-mortem specimens from the 1918 influenza pandemic showed that although many people were infected with this virus, of those that died the vast majority had a secondary bacterial pneumonia. Such complications are now recognised as a dangerous consequence of many inflammatory lung diseases. The innate immune rheostat determines the responsiveness of the immune system to infection. We aim to map the signalling pathways which influence the rheostat in the lung at homeostasis; and how prior infection with Respiratory Syncytial Virus or Influenza virus alters this to cause secondary bacterial pneumonia and sepsis. Our central hypothesis is that prior inflammation in the lung alters subsequent innate responsiveness by modulating specific immune regulatory pathways, and that the extent of this change is dictated by the severity of the first inflammatory insult. We show that susceptibility to bacterial complication extends far beyond the period of acute viral disease in all viral models studied. Concentrating on alveolar macrophage, the front line of defence in the lung, we observe that viral infection leads to Toll-like receptor desensitisation, an increase in the expression of innate negative regulators, and a dramatic change in the microRNA profile of these cells. Similar alterations in the microRNA profile of alveolar macrophage were observed following a variety of inflammatory insults, suggesting this represents a universal phenomenon. By manipulating these microRNAs it seems possible to reset the threshold of activation of alveolar macrophage, suggesting that these small molecules may be viable therapeutic targets.
Supervisor: Hussell, Tracy Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral