UC San Diego

Major pandemics of Influenza A have caused the deaths of several million people in the past century alone. Discovering treatments to combat influenza A infection could save many lives in the event of an outbreak. We are attempting to generate new ways of treating influenza by creating dominant negative (DN) inhibitors to the influenza non-structural protein, NS1, which has an important role in suppressing the host immune response and is critical for viral replication. We have generated a stock of Drosophila melanogaster carrying a genomic insertion of a NS1 transgene flanked by an N-terminal HA tag and a C-terminal Myc tag. Expression of NS1 conditionally in the wing using the yeast derived UAS/Gal4 system causes a visible wing phenotype including expansion between wing veins L3 and L4 and partial loss of L4. We have conducted a screen in which the mutagen delta 2-3 transposase was used to create deletions and truncations directed to the NS1 transgene in flies. From this screen, we have isolated two putative NS1 DN alleles that produce truncated NS1 proteins and can suppress the wing phenotype caused by the expression of the wild-type copy. Furthermore, these alleles produce no phenotype when expressed on their own indicating a low probability of serious off target effects if used as treatments in humans