Study uncovers immune defense system that shields the lungs from viral diseases

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• Source: Quadram Institute


• Date: 18 Mar,2021

Scientists have discovered a previously unknown arm of the immune defense system that protects the lung from lethal viral infections.

Respiratory diseases caused by viruses such as influenza A and SARS-CoV-2 cause harm not only through their own activities, but also from collateral damage as the immune system reacts to combat the infection.

A timely and proportionate response identifies viruses, isolating them in tiny vesicles called phagosomes which are then targeted for breakdown.

This has serious consequences for viral lung infections, as it leads to inflammation, fluid building up in the lungs and eventually death.

Given the effect 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 could protect against infections taking hold.

To address this teams in the Quadram Institute and universities of Liverpool, East Anglia (UEA), and Bristol have worked together to studythe immune response to influenza A virus infection in the lungs of mice. Animal models provide a way of understanding how the immune system functions, and as with SARS-CoV-2, animals might be a substantial reservoir for viruses which, if transferred to people, can activate pandemics.

Funded by the Biotechnology and Biological Sciences Research Council, they focussed on a newly characterised form of non-canonical autophagy known as LC3-associated phagocytosis (LAP) that recognises pathogens as they enter cells.

Professor Tom Wileman in the Quadram Institute has worked with Dr Penny Powell and Professor Ulrike Mayer at UEA to create a LAP-deficient mouse to examine viral infection. Unique to this study, the mice were designed to retain the standard autophagy machinery, and target LAP in immune cells, are the best available choice for understanding the precise role of this newly discovered immune defense.

Prof James Stewart at the University of Liverpool characterised the purpose of LAP by infecting the transgenic mice with influenza virus and studying the response to infection.

The mice were found to be more susceptible to the virus, with it triggering a 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 provided the answer by looking at the cells lining the surface of the lung. There was no difference in the way the virus initially binds to these cells, but they did see that non-canonical autophagy/LAP did slow the method by which the virus enters the cell. It may work by preventing the virus fusing with endosomes, which are the cell’s way of importing materials from outside.

Non-canonical autophagy/LAP is very likely to be significant as a primary defense against disease, where there isn’t any immunity from prior infections, especially in the specific case of flu and SARS-CoV-2.

Being able to describe this novel part of the immune defense system against respiratory infections in very exciting, especially given the current pandemic. We need to assess whether the same system provides similar protection in humans, but this does point to the possibility of developing new drugs that manipulate this non‐canonical autophagy to increase resistance at the lung surface, where it is most needed.”

Tom Wileman, Professor, University of East Anglia and Quadram Institute