Effect of Peroxisome Proliferation on Replication of Emerging RNA Viruses

Abstract

Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important emerging human pathogens that have disrupted global health. More therapeutic and prophylactic treatments for the diseases caused by the emerging viruses are needed. Expansion of our knowledge on the interplay between host cellular pathways and the viruses during infection will provide insights on how these viruses cause diseases and potentially on the development of antivirals. In this thesis, I used two different approaches to induce peroxisome proliferation in cells and investigated the antiviral effects of peroxisome proliferation on the replication of emerging viruses, including ZIKV and SARS-CoV-2. A major finding was that both over-expression of PEX11B in cells and inhibition of Wnt/β-catenin signaling pathway suppress the replication of ZIKV and SARS-CoV-2. This is in large part due to the enhanced induction of interferon (IFN) expression resulting from the expansion of the abundance of peroxisomes. Specifically, pre-infection treatment with the ten Wnt/β-catenin inhibitors reported in the thesis were shown to greatly reduce SARS-CoV-2 replication. Three of these inhibitors also blocked viral replication when added post infection. Together, this thesis work describes novel roles of Wnt/β-catenin signaling pathway inhibitors in peroxisome biogenesis and provide new avenues for therapeutic and even non-vaccine prophylactic development.