Matthew Melki, McMaster University

Matthew Melki (McMaster University, Mossman Lab)

Discovering & Evolving

The WNK-SPAK/OSR1 signaling pathway responds to changes in osmolarity to regulate ion transport. Upon activation, WNK kinases phosphorylate downstream kinases SPAK/OSR1, which in turn modulate the activity of ion cotransporters to restore ion balance. Stress proteins have a dual role in response to viral infection: they can assist in formulating an antiviral response or their functions can be hijacked by the invading virus to promote replication. As such, targeting host kinases as a means of developing novel antiviral treatments is becoming an increasingly important field to combat the highly mutative nature of viruses. WNK's ion modulation and antiviral roles, both implicated in the replication of viruses, highlight this pathway as a major virological research interest which is yet to be explored. I hypothesize that WNK signaling promotes the replication of multiple virus families by modulating viral protein accumulation. Using inhibitor WNK463, the effect of WNK activity inhibition on viral replication was tested in human fibroblast cells. Cells were infected with herpes simplex virus 1 (HSV-1) in the presence of WNK463 and single-step growth curves were generated over an infection period of 24 hours. Cell lysates were also collected for subsequent western blot analyses to quantify viral protein levels. Treatment of cells with WNK463 reduces HSV-1 replication and protein accumulation. Furthermore, knockout of SPAK also reduces viral replication both in vitro and in vivo. These results suggest the involvement of WNK signaling in promoting viral replication and further experimentation will expand on these findings by continuing to elucidate the mechanism.