The role of LC3-associated phagocytosis during virus infection

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LC3-associated phagocytosis (LAP) is a recently-characterised phagocytic pathway that plays important roles during immunity to infectious agents including viruses. LAP shares many features with the well-characterised autophagy pathway but differs in signalling events upstream of LC3 recruitment to membranes. Thus, the precise role played by each pathway 'in vivo' has been very difficult to dissect. The unique aspect of this grant proposal is based on our generation of mice that are deficient in LAP, but have normal autophagy. This allows us to focus specifically on the role played by LAP in the control of viral infection. Our preliminary data using Influenza A virus (IAV) infection of LAP deficient mice reveal that there are higher virus titres, more inflammation and more clinical signs in the absence of LAP. We therefore believe that LAP plays an important role in host defence in the respiratory tract. The aims of this project are to:1. Discover the precise way that LAP acts in the defence mechanisms to IAV infection. This will involve comparing the progress of viral infection in genetically modified mice deficient in LAP with normal mice. We will also study whether LAP influences inflammatory responses, various types of immune responses (antibody and cytotoxic T cell) as well as other anti-viral responses such as interferon.2. Discover whether LAP specifically in macrophages or epithelial cells plays a role in the defence against IAV. To do this, we generate conditional knockout mice that are lacking LAP in macrophages but not in all other tissues. These mice will be infected with IAV and then investigated as in Aim 1.The results will significantly enhance our understanding of fundamental aspects of defence to virus infection as well as aspects of respiratory biology. The research will be carried out at the Universities of Liverpool and UEA by a multi-disciplinary team comprising members of the Medical and Veterinary Faculties using well-equipped facilities currently situated at these sites. Defects in autophagy are associated with aberrant host defence, inflammatory disease and age-related disorders. It is possible that a defect in LAP, rather than autophagy, accounts for some of these pathological conditions. Characterisation LAP separate from autophagy, will allow examination of pathologies linked to autophagic machinery in a new light. In turn this may lead to novel approaches to improving antiviral therapies or therapeutic interventions against the consequences of viral infection