Research

Ducks are the primary host of influenza virus. They can be infected with all strains of influenza, and most cause them little harm. We are interested in both the host-pathogen interactions that permit re-infection, and understanding how the duck successfully clears the virus. Lessons from ducks may identify new strategies to prime our immune defenses against deadly influenza.



Selected publications

Pattern Recognition Receptor Signaling and Innate Responses to Influenza A Viruses in the Mallard Duck, Compared to Humans and ChickensMallard ducks are a natural host and reservoir of avian Influenza A viruses. While most influenza strains can replicate in mallards, the virus typically does not cause substantial disease in this host. Mallards are often resistant to disease caused by highly pathogenic avian influenza viruses, while the same strains can cause severe infection in humans, chickens, and even other species of ducks, resulting in systemic spread of the virus and even death. The differences in influenza detection and antiviral effectors responsible for limiting damage in the mallards are largely unknown. Domestic mallards have an early and robust innate response to infection that seems to limit replication and clear highly pathogenic strains. The regulation and timing of the response to influenza also seems to circumvent damage done by a prolonged or dysregulated immune response. Rapid initiation of innate immune responses depends on viral recognition by pattern recognition receptors (PRRs) expressed in tissues where the virus replicates. RIG-like receptors (RLRs), Toll-like receptors (TLRs), and Nod-like receptors (NLRs) are all important influenza sensors in mammals during infection. Ducks utilize many of the same PRRs to detect influenza, namely RIG-I, TLR7, and TLR3 and their downstream adaptors. Ducks also express many of the same signal transduction proteins including TBK1, TRIF, and TRAF3. Some antiviral effectors expressed downstream of these signaling pathways inhibit influenza replicat...
Influenza PB1-F2 Inhibits Avian MAVS SignalingRIG-I plays an essential role in the duck innate immune response to influenza infection. RIG-I engages the critical adaptor protein mitochondrial antiviral signaling (MAVS) to activate the downstream signaling pathway. The influenza A virus non-structural protein PB1-F2 interacts with MAVS in human cells to inhibit interferon production. As duck and human MAVS share only 28% amino acid similarity, it is not known whether the influenza virus can similarly inhibit MAVS signaling in avian cells. Using confocal microscopy we show that MAVS and the constitutively active N-terminal end of duck RIG-I (2CARD) co-localize in DF-1 cells, and duck MAVS is pulled down with GST-2CARD. We establish that either GST-2CARD, or duck MAVS can initiate innate signaling in chicken cells and their co-transfection augments interferon-beta promoter activity. Demonstrating the limits of cross-species interactions, duck RIG-I 2CARD initiates MAVS signaling in chicken cells, but works poorly in human cells. The D122A mutation of human 2CARD abrogates signaling by affecting MAVS engagement, and the reciprocal A120D mutation in duck 2CARD improves signaling in human cells. We show mitochondrial localization of PB1-F2 from influenza A virus strain A/Puerto Rico/8/1934 (H1N1; PR8), and its co-localization and co-immunoprecipitation with duck MAVS. PB1-F2 inhibits interferon-beta promoter activity induced by overexpression of either duck RIG-I 2CARD, full-length duck RIG-I, or duck MAVS. Finally, we show that the effect of PB1-F2 on mitochondria abrogates TRIM25-mediated ubiquitination of RIG-I CARD in both human and avian cells, while an NS1 variant from the PR8 influenza virus strain does not.