VIDO research program area: Emerging Diseases & Microbial Virulence
Overview Influenza viruses continue to pose a severe threat worldwide. The major difficulty in defending against influenza virus infection is the high genetic variability of the virus. This results in a rapid generation of reassortant viruses that escape the immunity acquired against previous virus strains, or that gain resistance to antiviral agents. During virus infection, virus-host interactions determine the course of the virus life cycle and pathogenesis. One important strategy from the perspective of the virus is to activate cellular signalling pathways and hijack the cellular machinery to augment viral replication and propagation. Thus, cellular events that are essential for efficient virus replication and propagation might be the target for anti-influenza interventions. By genetically changing influenza viruses via reverse genetics technology, we study how viral genes and gene products activate cellular signalling pathways and how the pathways regulate virus propagation and pathogenesis.
Background:
Influenza viruses continue to pose a severe threat worldwide. The major difficulty
in defending against influenza virus infection is the high genetic variability
of the virus. This results in a rapid generation of reassortant viruses that
escape the acquired immunity against previous virus strains or gain resistance
to antiviral agents. During virus infection, virus-host interaction determines
the virus life cycle and pathogenesis. One important strategy from the perspective
of the virus is to activate cellular signalling pathways and hijack the cellular
machinery to augment viral replication and propagation. Thus, cellular events
that are essential for efficient virus replication and propagation might be
the target for anti-influenza interventions.
Our research is focusing on influenza virus-host interactions. Specifically,
by genetically changing influenza viruses via reverse genetics technology, we
study how viral genes and gene products activate cellular signalling pathways
and how the pathways regulate virus propagation and pathogenesis.
Objectives:
To identify the molecular mechanism of how influenza virus infection
activates certain cellular signalling pathways.
To identify how the activated cellular signalling pathways regulate influenza
virus infection and pathogenesis
Progress:
We found that Akt phosphorylation was elevated in the late phase of influenza A/PR/8/34 infected human lung carcinoma cells (A549). The PI3K-specific inhibitor LY294002 could suppress Akt phosphorylation, suggesting that influenza A-virus-induced-Akt phosphorylation is PI3K-dependent. We demonstrated that the influenza A virus NS1 protein is responsible for activation of the cellular PI3K/Akt pathway by direct interaction with the p85 subunit of PI3K. Furthermore, the binding domain in p85, and binding motifs in the NS1 protein, were identified (J Gen Virol. 2007, 88:13-8; J Virol. 2007 Dec; 81(23):12730-9).
Next, we demonstrated that blockage of PI3K/Akt activation by LY294002 led to reduction in virus yield. Moreover, in the presence of LY294002, both viral RNA and viral protein expression were suppressed. We demonstrated that PI3K/Akt signalling pathway plays a role in influenza virus propagation (J Gen Virol. 2007 Mar; 88: 942-50. 2007 publications).
Project Leader:
