Uncovering the control of pathogenic herpesviruses by human and viral circular RNAs

Circular RNAs (circRNAs) play key co- and post-transcriptional roles in many human diseases, including cancer and neurological disorders. I was one of the first to discover that circRNAs regulate virus infection. I also identified virus-encoded circRNAs. The low immunogenicity of circRNAs presents them as ideal viral tools to manipulate gene expression. My research revealed a host circRNA (circRELL1) that is induced by many herpesviruses, promotes the survival of latently infected cells, and suppress the lytic cycle of an oncogenic Kaposi sarcoma herpesvirus. While the significance of circRNAs on latency establishment is well documented, an understanding of the regulatory mechanisms is lacking. Further, effects of viral and host circRNAs on immunity and oncogenesis needs investigation since they are critical aspects for herpesviruses. As a first step, I employed high-throughput approaches including a CRISPR-based method, to identify circRNA-associated proteins and RNAs. These data led me to the hypothesis that herpesviruses exploit circRNAs to control mRNA stability and modulate signaling pathways. By integrating biochemical and phenotypic analyses, I aim to obtain mechanistic insights into how human and herpesvirus circRNAs regulate the viral life cycle, antiviral immunity, and tumor microenvironment. This research will lead to a fundamental understanding of how circRNAs impact virus infection.