The role of LC3-associated phagocytosis during virus infection
Lead Research Organisation:
University of East Anglia
Department Name: Norwich Medical School
Abstract
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Technical Summary
LC3-associated phagocytosis (LAP) is a recently characterised phagocytic pathway that plays important roles during innate defence and immunity to pathogens. LAP shares many components 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.
We will use mice deficient in LAP, and mice where LAP is specifically removed from macrophages or epithelial cells. The transgenic models will be infected with IAV and the pathogenesis of infection analysed for virological, inflammatory and immunological parameters. IAV is relevant to disease in animals and has good sets of specific reagents that will allow the study of the host response in mice. This will allow us to determine the role played by LAP during an acute, cytopathic infection in the respiratory tract that is normally cleared rapidly generating immunity to re-infection.
The results will significantly enhance our understanding of fundamental aspects of host responses to virus infection in the lung as well as respiratory biology. In turn this may lead to novel approaches to improving antiviral therapies or therapeutic interventions against the consequences of viral infection.
We will use mice deficient in LAP, and mice where LAP is specifically removed from macrophages or epithelial cells. The transgenic models will be infected with IAV and the pathogenesis of infection analysed for virological, inflammatory and immunological parameters. IAV is relevant to disease in animals and has good sets of specific reagents that will allow the study of the host response in mice. This will allow us to determine the role played by LAP during an acute, cytopathic infection in the respiratory tract that is normally cleared rapidly generating immunity to re-infection.
The results will significantly enhance our understanding of fundamental aspects of host responses to virus infection in the lung as well as respiratory biology. In turn this may lead to novel approaches to improving antiviral therapies or therapeutic interventions against the consequences of viral infection.
Planned Impact
Respiratory virus infections are of global significance to both the human and animal populations. The zoonotic potential of influenza and the implications of emerging new strains are well recognised by both the scientific community and the general public. Improved understanding of the pathogenesis of infection and the host response to these pathogens is critical in improving treatment and management of respiratory disease and the associated morbidity and mortality. This work aims to further this understanding by looking at the role of LC3-associate phagocytosis (LAP) in the innate and adaptive responses of the host respiratory tract following infection with influenza virus.
The academic impact of this work therefore will be to further the knowledge of the host response to viral infection, providing the foundations of academic knowledge and understanding on which future advancements in treatment and disease control can be built. The use of the multi-disciplinary approach as proposed here brings together expertise in cell biology, molecular virology, immunology and veterinary pathology, thereby maximising the potential outputs of the research. This is also advantageous to the RA in providing the experience and training involving multiple fields fostering a multi-disciplinary approach and its advantages for enhanced, productive science as well as allowing them to develop a range of transferable skills that will enhance their career development. This is achieved by collaboration between the Universities of East Anglia and Liverpool.
The societal impact of furthering the understanding of the host response to infection with Influenza virus on the health of the individual and the wider population is significant. Contribution to the improved treatment of individual high risk patients where infection with Influenza virus has a higher morbidity and mortality than the general population, or increased understanding of the risk factors associated with epidemic strains, both are important in the future of prevention and control of Influenza infection, in both veterinary species and the human population.
The academic impact of this work therefore will be to further the knowledge of the host response to viral infection, providing the foundations of academic knowledge and understanding on which future advancements in treatment and disease control can be built. The use of the multi-disciplinary approach as proposed here brings together expertise in cell biology, molecular virology, immunology and veterinary pathology, thereby maximising the potential outputs of the research. This is also advantageous to the RA in providing the experience and training involving multiple fields fostering a multi-disciplinary approach and its advantages for enhanced, productive science as well as allowing them to develop a range of transferable skills that will enhance their career development. This is achieved by collaboration between the Universities of East Anglia and Liverpool.
The societal impact of furthering the understanding of the host response to infection with Influenza virus on the health of the individual and the wider population is significant. Contribution to the improved treatment of individual high risk patients where infection with Influenza virus has a higher morbidity and mortality than the general population, or increased understanding of the risk factors associated with epidemic strains, both are important in the future of prevention and control of Influenza infection, in both veterinary species and the human population.
Publications
De Faveri F
(2020)
LAP-like non-canonical autophagy and evolution of endocytic vacuoles in pancreatic acinar cells.
in Autophagy
Fletcher K
(2018)
The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes.
in The EMBO journal
Jones EJ
(2020)
The Uptake, Trafficking, and Biodistribution of Bacteroides thetaiotaomicron Generated Outer Membrane Vesicles.
in Frontiers in microbiology
Serramito-Gómez I
(2020)
Regulation of cytokine signaling through direct interaction between cytokine receptors and the ATG16L1 WD40 domain.
in Nature communications
Shimmon G
(2021)
Autophagy impairment by African swine fever virus
in Journal of General Virology
Wang Y
(2022)
Control of infection by LC3-associated phagocytosis, CASM, and detection of raised vacuolar pH by the V-ATPase-ATG16L1 axis
in Science Advances
Wang Y
(2021)
Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus.
in The EMBO journal
| Description | Wehave uncovered a previously unknown arm of the immune defence system that protects the lung from lethal viral infections. Respiratory diseases caused by viruses such as influenza A and Sars-CoV-2 cause damage not just through their own actions, but also from collateral damage as the immune system reacts to fight the infection and stop the virus reproducing. This process also triggers production of cytokines to alert the immune system that sometimes escalates into a lethal cytokine storm. Given the impact of respiratory conditions, brought into sharp focus by the COVID-19 pandemic, there's a clear need to fully understand the complexities of this immune response to develop better treatments or targets for drugs that can protect against infections taking hold. To address this teams from the Quadram Institute, University of East Anglia (UEA), University of Liverpool and the University of Bristol have worked together to study the immune response to influenza A virus infection in the lungs of mice. ProfessorTom Wileman at the Quadram Institute and Dr Penny Powell and Professor Ulrike Mayer at UEA developed a LAP-deficient mouse to study viral infection. Mice were challenged with influenza virus by Professor James Stewart at the University of Liverpool's Institute of Infection and Global Health. They were found to be much more susceptible to the virus, with it triggering cytokine storm leading to pneumonia. The researchers showed that LAP prevented a lethal cytokine storm by supressing lung inflammation. Dr Yohei Yamauchi and colleagues from the University of Bristol showed that non-canonical autophagy/LAP slowed the fusion of IAV with endosomes. Non-canonical autophagy/LAP is likely to be important as a first defence against infection, where there is no immunity from previous infections, especially in the specific case of influenza and SARS-CoV-2. It is important to assess whether the same system provides similar protection in humans and whether the development of new drugs that manipulate this non-canonical autophagy can prevent lung inflammation. |
| Exploitation Route | Non-canonical autophagy/LAP is likely to be important as a first defence against lung infection, where there is no immunity from previous infections, especially in the specific case of influenza and SARS-CoV-2. It is important to assess whether the same system provides similar protection in humans and whether the development of new drugs that manipulate this non-canonical autophagy can prevent lung inflammation |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Transfer of mice deficient in LAP |
| Organisation | Lanzhou Veterinary Research Institute |
| Country | China |
| Sector | Learned Society |
| PI Contribution | Mice deficient in LAP generated at UEA/QIB have been sent to Lanzhou Veterinary Research Institute (LVRI). T. Wileman, P. S. Carding, Regis Stentz from Norwich Research Park, and James Stewart from University of Liverpool visited State Key Laboratory of Lanzhou Veterinary Research Institute (LVRI) , and Pasteur Institute Shanghai in June 2016 to discuss research projects and collaboration. T. Wileman, P. Powell, S. Carding, Regis Stentz from Norwich research Park, and James Stewart from University of Liverpool visited three research institutes (Institute of Microbiology, Beijing Academy of Sciences, State Key Laboratory of Lanzhou Veterinary Research Institute, Northwest Agricultural and Forestry University,Yangling, Shaanxi) in October 2018 to discuss further research projects and collaboration. Mice deficient in LAP generated at UEA/QIB have been sent to University of New Mexico, USA, St Judes Medical Centre, Memphis USA, University of South Florida. USA, |
| Collaborator Contribution | LAP deficient mice will be used in infection studies focusing on Foot and Mouth Disease virus at LVRI, and possibly Zika virus at Pasteur Institute in Shanghai. Scientists from the Chinese Academy of Agricultural Sciences (Zhidong Zhang, Yanmin Li, Xiaodong Qin) and Gang Long from Pasteur Institute Shanghai, visited Norwich Research Park 06:2017 to discuss collaborative work. Dr Yang Yang from LVRI has been sent on a six month secondment (October 2018-May 2019) to UEA to learn how to characterise LAP deficient mice. Mice deficient in LAP will be used in studies of infection and age dependent cognitive decline DOI: 10.1126/sciadv.abb9036 |
| Impact | DOI: 10.1126/sciadv.abb9036 |
| Start Year | 2019 |