Doctor of Philosophy
Influenza virus is a threat to public health on a global scale. Each year, millions of people are infected with influenza virus leading to hundreds of thousands of deaths. Despite progress in developing anti-influenza drugs, every antiviral compound used has caused influenza strains to mutate and become resistant to the drug. In order to improve our defenses against influenza virus, novel research strategies are needed. The innate immune system is the first line of defense against incoming pathogens. Many signaling networks are involved in coordinating an efficacious response to viral insult. We have found that lipid signaling through phospholipase D is critical to influenza pathogenesis. Influenza virus exploits this signaling to quickly infect human lung cells and evade the host antiviral response. By inhibiting this process, we observed a marked protection from infection. One of the critical molecules of the protective innate immune response after phospholipase D inhibition is interferon regulatory factor 3. Surprisingly, we found that mice missing this protein are more likely to survive a lethal influenza infection. This survival advantage depends on an amplified adaptive immune response. We are currently investigating this crosstalk between the innate and adaptive immune systems. One of the most potent direct antiviral effector molecules in the innate arsenal is myxovirus resistance gene 1. While this protein is generally considered to function by binding directly to viral proteins and inhibiting their functions, we have uncovered an unrecognized activity of this protein. We show that basal expression of this protein is critical in the induction of the innate immune response, and it is potentially involved in the signaling network that is constructed in response to influenza infection. These results help define the critical events mediating the host-virus interaction in infected epithelial cells. Future research for new antiviral strategies can exploit these novel pathways to enhance host responses and limit viral replication efficiency.
Dissertation or thesis originally submitted to the local University of Memphis Electronic Theses & dissertation (ETD) Repository.
Oguin, Thomas Howard III, "Innate Immune Induction in Influenza Infection" (2015). Electronic Theses and Dissertations. 1169.