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Title: Lung innate homeostasis and susceptibility to viral induced secondary bacterial pneumonias
Author: Goulding, John Charles
ISNI:       0000 0004 2681 3720
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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Influenza A virus causes significant and well publicised morbidity and mortality as a single infection. However, in combination with a secondary bacterial super infection the resulting prognosis is worse and can result in hospitalisation or death. Despite extensive clinical and epidemiological evidence, the precise immunological mechanism(s) responsible for increasing susceptibility to secondary bacterial infections remain unknown. Possible mechanisms include disruption to the epithelial barrier, up-regulation of bacterial adhesion receptors, virus-induced immune suppression or a combination of all three. In this thesis we examine a novel hypothesis that suggests influenza virus infection alters the lung homeostatic microenvironment resulting in a state of immune unresponsiveness that increases susceptibility to subsequent respiratory bacterial infections. This thesis demonstrates that respiratory bacterial complications only arise once influenza has caused significant respiratory damage and can occur many days after viral elimination. We also demonstrate that influenza infection results in a long term desensitisation of alveolar macrophage responses to subsequent bacteria and their products. Furthermore, in an attempt to resolve viral associated inflammation, the airway inadvertently over regulates by enhancing an innate immune negative regulator, CD200R, resulting in a transient state of immune hypo-responsiveness. Removal of this single receptor limits bacterial burden and completely prevents lethal bacteraemia. Finally, we provide preliminary data that suggests airway antimicrobial peptide expression is altered during an influenza infection and that innate immune status of the host can influence commensal bacteria communities of the upper respiratory tract. This thesis highlights that infection history can significantly influence host immunity to subsequent infections and how an increased awareness of this could lead to more targeted use of existing antimicrobial therapies and the development of much needed novel therapeutics. Adjustment of the level of innate responsiveness may therefore provide a novel opportunity to prevent life-threatening consequences of lung influenza virus infection.
Supervisor: Hussell, Tracy Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral