Understanding the Molecular Determinants of Reassortment in Orthobunyaviruses and Phleboviruses.

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Project Summary/Abstract Genome reassortment drives the diversity we see in segmented RNA viruses. Unlike recombination, intact genes are readily exchanged between two co-infecting viruses, resulting in their rapid evolution. Reassortment amongst influenza viruses is a well-established driver of host range and virulence. Though reassortment occurs frequently amongst bunyaviruses and can result in highly virulent reassortants such as Ngari virus, the underlying mechanisms are unknown. Understanding how these viruses reassort and modify virulence will allow us to predict potential virus emergence or modulations in host range allowing potential species jumps. The goal of this project is to investigate the molecular determinants of reassortment and virulence amongst orthobunyaviruses and phleboviruses. These are tri-segmented negative sense RNA viruses with Small (S), Medium (M) and Large (L) segments encoding the nucleocapsid protein, glycoproteins GnGc and a viral polymerase (L protein), respectively. Some viruses also encode nonstructural proteins on the S and/or M segments. Aim 1, will investigate segment compatibility amongst the priority pathogens Severe fever with thrombocytopenia syndrome virus and Heartland virus, using a forward and reverse genetics approach. Aim 2, will investigate homologous and heterologous segment dynamics within infected cells. Aim 3, will investigate the virulence of natural reassortants of Oropouche virus and potential reassortants of SFTSV and HRTV. These studies are of significant importance, as only by understanding the fundamental aspects of the biology of these viruses will we be able to understand the molecular determinants of their reassortment. This proposal will support my long-term career goal of understanding novel virus emergence and evolution. My mentorship team consists of Professor Paul Duprex, an expert in paramyxoviruses and cross-species viral transmission, Dr. Anita McElroy, an expert in Rift Valley fever virus (RVFV) transmission and immunology, Dr. Amy Hartman, an expert in RVFV pathogenesis in rats and monkeys and Dr. Seema Lakdawala, an expert in influenza virus biology and reassortment. With the support of strong mentors and collaborators I will receive training in the skills required to complete the proposed aims. Upon completion of the K99 phase I will be in a strong position to pursue an independent and successful research position contributing to the bunyavirus field.