FLUPHAGY · Regulation of Macroautophagy by viral Pathogens

Regulation of Macroautophagy by viral Pathogens

Influenza infections kill around 300.000 people each year. Due to its ability to reassort with viruses from other animal species and its mutational drift, long lasting immunity cannot be established. Hence, society is in great need of new therapy strategies to fight Influenza outbreaks. Eukaryotic cells possess two major processes for the degradation of intracellular material, the proteasome and autophagy. Autophagy is characterized by the formation of double-membraned vesicles termed ‘autophagosomes’ which engulf cytosolic material (proteins and entire organelles) and fuse with the lysosome to form so called ‘autophagolysosomes’. The main molecular players of this process are called ‘autophagy-related genes (Atg)’. The classical marker for autophagosomes is ATG8, also called LC3. Autophagy plays a major role in providing the cell with energy in times of starvation, but it is also crucial in immunity. In regards to innate immunity, it is involved in pathogen sensing, inflammasome activation and regulation of pattern recognition receptor (PRR) signaling. In regards to adaptive immunity, it was shown to play a role in antigen presentation. Because autophagy has such an important role in providing antigens for presentation to T cells, pathogens have developed evasion strategies targeting autophagy. Understanding this intricate relationship will help in the development of novel vaccination and therapy strategies. Influenza, in particular, alters the autophagy machinery, which is involved in delivery and processing of antigens at steady-state. The relevance of these alterations for the immunogenicity and pathology of the virus were the main objectives investigated in the project ‘Fluphagy’. Recently, it has been shown that macroautophagy is required for memory B, memory T, effector T and Treg cell survival at steady-state and in influenza infection, indicating that the role of autophagy in influenza infection might be cell type dependent. Influenza infects alveolar macrophages and epithelial cells in the lung. Influenza is able to arrest the fusion of autophagosomes with lysosomes in vitro, the physiological relevance of it, however, remains unknown. Our group has shown that in macrophages and dendritic cells autophagy deficiency leads to improved antigen presentation due to increased cell surface levels of MHC class I (Loi et al Cell Report 2016). I have investigated the role of macroautophagy during influenza infection of epithelial cells in vivo using a mouse model of inducible knockout of ATG5 in alveolar type II cells. Autophagy deficiency led to an increase in viral titer and enhanced pathology after infection with H1N1 influenza strain PR8. As a result, influenza-specific antibody levels were increased. However, this phenotype seems to be virus subtype specific. The molecular mechanisms underlying this phenotype require further elucidation. Understanding the intricate relationship between influenza and the macroautophagy machinery in alveolar type II cells, which get directly infected by the virus, might advance the search for new ways to target Influenza infections. Every season Influenza epidemics arise due to the virus undergoing antigenic shift. Vaccines are time consuming in their production, hence, predictions on the strains to arise each year have to be made way in advance. These predictions are not always accurate and as a result society faces incomplete protection during some Influenza seasons. Understanding the interplay between virus and host cell in more detail might allow for novel vaccination and/or therapeutic strategies against Influenza infections. This might not only lower the number of infected people each year, but might also protect those that suffer from severe symptoms after infection, e.g. elderly or immunocompromised patients.

Data: CORDIS, © European Union