Leveraging host peroxisome biogenesis and activity to dampen replication of emerging RNA viruses - an approach towards host directed antiviral development.

Viral outbreaks can impose devastating burdens on our social and economic systems. Since 2015, emerging alphavirus and coronavirus outbreaks have resulted in more than 50 million human infections. While alphaviruses cause encephalitis and arthritis, coronaviruses such as SARS-CoV-2, can cause severe acute respiratory diseases such as COVID-19. Unfortunately, there are no licensed specific antiviral therapeutics or any approved vaccines yet. To address the need for therapeutics against alphaviruses and coronaviruses, I will investigate how these pathogens affect the formation and functions of a host organelle called the peroxisome. Peroxisomes are best known for controlling lipid metabolism and reactive oxygen species and their activity and abundance can be modulated using a variety of clinically tested and licensed drugs. However, recent studies revealed that peroxisomes are important for the interferon pathway, a critical response by our cells that provides natural protection against many types of viruses. Moreover, the Hobman lab showed that increasing peroxisome numbers dramatically inhibits replication multiple viruses, including Zika virus, a flavivirus that was responsible for a large epidemic in 2015. Viruses evade the interferon induction and signaling pathways by hijacking cellular proteins. Because peroxisome biogenesis and activity are controlled by multiple cellular pathways, it is critical to understand how different RNA viruses affect these processes. In doing so, it should be possible to devise therapeutic approaches based on drugs that induce peroxisomes through specific pathways. Using a global approach, I will determine how virus-encoded proteins from alphaviruses (Mayaro virus; Chikungunya virus) and coronaviruses (SARS-CoV-2) interact with cellular pathways that affect peroxisomes. It is expected that this work will lead to the development of broad-spectrum antiviral strategies that activate the interferon system by upregulating peroxisomes.