Small RNA-mediated warfare between viruses and their hosts

PROJECT SUMMARY Non-coding RNAs (ncRNAs) constitute the majority of RNAs present within the human cell, and are potent regulators of cellular processes, including translation, splicing, and post-transcriptional messenger RNA (mRNA) control. Like humans, viruses produce ncRNAs, whose functions are still largely unknown. Given that viruses evolved to maximize the information contained within their small genomes, all viral ncRNAs are postulated to be functional. Our lab studies the mechanisms by which small viral ncRNAs modulate host and viral processes, the knowledge of which will contribute to the development of new approaches to treat human disease. In the next five years, we will elucidate the roles of two distinct viral ncRNAs classes: small nuclear RNAs (snRNAs) expressed by an oncogenic g-herpesvirus (Project 1), and a microRNA (miRNA) produced by SARS-CoV-2, a virus that causes acute respiratory disease (Project 2). g-herpesviruses are DNA viruses, which during latency induce host cell transformation and oncogenesis. The latent viral genes produce several proteins and multiple ncRNAs. During its latency, herpesvirus saimiri, a classic g-herpesvirus, expresses seven snRNAs, known as HSURs. Unlike human snRNAs, HSURs were not linked to mRNA splicing, but instead to regulating host RNA levels in the cytoplasm. Interestingly, our results indicate that HSURs predominantly localize to the nucleus, where their roles remain unknown. Additionally, we observe that HSURs selectively translocate host cytoplasmic RNA-binding proteins into the nucleus. In Project 1, we will investigate the nuclear roles of viral snRNAs to explore unknown functions for host RNA-binding proteins and to gain insights into g-herpesviral transformation. SARS-CoV-2, a large RNA virus, is the causative agent of the coronavirus disease 2019 and the source of the current pandemic. We and others have recently discovered a miRNA expressed by SARS-CoV-2, named CoV-miR-O7a, which downregulates host genes involved inter alia in interferon signaling. Our preliminary data show that CoV-miR-O7a is abundantly present inside SARS-CoV-2 virions. We hypothesize that CoV-miR-O7a (and perhaps other ncRNAs) are selectively incorporated into virions to allow for early manipulation of host gene expression. In Project 2, we will investigate the mechanism and significance of viral miRNA incorporation into nascent virions to understand as yet unknown aspects of SARS-CoV-2 pathogenesis and to describe the previously unexplored way in which viruses inhibit host antiviral responses. Our multidisciplinary approaches, combined with the flexibility of MIRA funding, will lead to the establishment of a unique research program centered around understanding of small RNA biology in the context of viral infection. In elucidating functions of small viral ncRNAs, this study will advance the fields of RNA biology and virology. Such knowledge can lead to identification of novel targets for treatment of viral disease, including virally-induced cancers.