Delineating Host Processes and Protection Mechanisms in Influenza Virus Infections

Viruses are obligate intracellular pathogens and thus must use host processes for their replication. Cell death is a common consequence of infection by many viruses, including influenza. Much is known about aspects of virus replication but we are only beginning to understand how host processes are affected by virus infection. Most host-directed process delineation has involved microarray analyses. We are complementing these genomic studies with proteomic studies. Host protein alterations induced by influenza virus infection have been determined by quantitative and functional assays in continuously-cultured and in primary cell cultures. In addition, genome-wide positive selection strategies have identified a small number of host proteins, knockdown of which protects cells from influenza virus-mediated death. Most of the proteins identified in these various screens map into a few well defined cellular pathways, and key nodes, including NF-κB, Akt, ERK1/2 and PI3K. More detailed analyses were performed on the cellular proteins BAD, MxB, TNFSF12/13 and USP47 because knockdown of any of these fully protected cells from infection by any of several types of influenza viruses including pandemic H1N1. BAD is a critical controller of the intrinsic apoptosis pathway. Influenza viruses carefully modulate BAD phosphorylation and apoptosis in a temporal manner to promote their replication. Mx proteins are GTPases in the dynamin superfamily and they appear to affect virus replication and viral protein trafficking. TNFSF13 is a member of the tumour necrosis factor ligand superfamily that is over-expressed in various tumours. Its knockdown abolishes a late step in influenza virus maturation. USP47 is a ubiquitin carboxyl-terminal hydrolase that promotes viral entry into cells.