Callum Magill, Queens University

Callum Magill (Queens University), Trinity H. Tooley(Queens University), Che C. Colpitts (Queens University)

Fighting & Responding

The ongoing outbreak of avian influenza A virus (IAV) is a serious threat to public health. A promising research area is the development of broad-spectrum host-targeting antivirals (HTAs). As HTAs can be effective against a wide range of viruses, there is no requirement to identify and study the virus outbreak before responding. Thapsigargin (Tg) is one such HTA with broad-spectrum antiviral activity, although its antiviral mechanisms have remained unclear. Here, we aimed to clarify its antiviral mechanism against IAV using PR8 as a model. We have shown that in A549 and Calu-3 cell lines, Tg potently inhibits IAV infection at doses as low as 5nM without affecting cell viability. Tg decreases viral titer, but has limited effect on viral gene or protein expression, indicating a post-transcription block to infection. Tg has been shown to enhance the expression of interferon-stimulating genes (ISGs) following stimulation, as well as inducing ER stress, which in turn induces the unfolded protein response (UPR), providing two potential routes that could inhibit IAV infection. Preliminary results indicate no difference in expression of two representative ISGs (MX1 or RSAD2) between Tg or DMSO control in A549 cells infected with IAV. Work is ongoing using UPR pathway knockdown cell lines to determine the role of each pathway in the restriction of IAV infection by Tg treatment. We are currently testing the role of UPR activation by comparing the effect of tunicamycin and Tg on IAV infection. These findings contribute to understanding the antiviral mechanisms of a broad-spectrum HTA.