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The innate immune rheostat : miRNA and negative regulation pathways which determine susceptibility to secondary bacterial complication

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Title: The innate immune rheostat : miRNA and negative regulation pathways which determine susceptibility to secondary bacterial complication
Authors: Godlee, Alexandra Elisabeth Clare
Item Type: Thesis or dissertation
Abstract: 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.
Issue Date: 2012
Date Awarded: Oct-2012
URI: http://hdl.handle.net/10044/1/17765
DOI: https://doi.org/10.25560/17765
Supervisor: Hussell, Tracy
Sponsor/Funder: Wellcome Trust (London, England)
Department: National Heart and Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses



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