HPAl, PB1-F2 en PA-X (KB-12-005.01-036)

Influenza A viruses are important pathogens with significant impact on animal and human health. Highly pathogenic avian influenza (HPAI) viruses of subtypes H7  and H5 continue to spread globally, causing death of millions of poultry, and pose a major public health threat. Therefore, it is of interest to study avian influenza virus infection in more detail, focussing on specific host mechanisms that determine disease susceptibility and pathogenesis.

Similar to many other viruses, Influenza A viruses have developed strategies to counteract the host cell's anti-viral response, especially the activation of the IFN-I system and the activity of its downstream effectors. An eminent role of the viral non-structural protein 1 (NS1) as an IFN-I antagonist and pathogenicity factor of IAV has been well established. A further pathogenicity factor, the polymerase basic protein 1-frame 2 (PB1-F2) protein was first described 10 years ago as a pro-apoptotic viral protein and has recently been shown to promote the onset of deleterious pro-inflammatory processes in mice. Interestingly, this protein seems to interfere with different pathways in mammalian and avian species. Because virtually all avian influenza viruses encode full-length PB1-F2 proteins, whereas PB1-F2-truncations are frequently found in mammalian isolates, it can be speculated that PB1-F2 may also be implicated in the process of pathogenicity and bird-to-bird transmission.

Recently, it was shown that the translation of the mRNA that encodes the PA subunit of the viral RNA polymerase complex, generates another protein (PA-X) that consists of the amino-terminal 191 amino acids of PA fused to 61 amino acids that result from a +1 reading frameshift. It has been shown that PA-X selectively degrades host mRNAs, abrogating their translation and reducing expression of short-lived cellular proteins such as immunological effector proteins. PA-X exhibits remarkable sequence conservation, although it does come in two forms, with many strains of the recently introduced swine-origin influenza viruses possessing a stop codon that truncates PA-X by 20 residues.
The goal of this project is to examine the immune modulating functions of the PB1-F2 and PA-X accessory proteins of highly pathogenic H5 and H7 avian influenza viruses (HPAIV) and to find out whether these proteins are involved in determining pathogenicity and disease susceptibility. To this end we will use mutants viruses that are unable to produce these proteins.