EVALUATING VIRAL ENTRY MECHANISMS OF EMERGING PARAMYXOVIRUSES

217 pagesThe Paramyxoviridae family includes many RNA viruses that collectively have a broad host range, including birds, fish, and mammals. Paramyxoviruses can productively infect a wide range of animal hosts and may be transmitted through the respiratory tract. The mammalian paramyxoviruses, Nipah virus (NiV) and Feline Morbillivirus (FeMV) belong to the Henipavirus and Morbillivirus genera, respectively. In addition to the highly virulent NiV, over twenty henipa-like viruses have recently been discovered globally. There are three additional species in the Henipavirus genus, with less than a decade since their discovery, including Cedar virus (CedV), Ghana virus (GhV), and Mojiang virus (MojV). Henipaviral host cell entry is coordinated by two viral surface glycoproteins: the tetrameric receptor binding protein (G) and the trimeric fusion glycoprotein (F). G consists of four domains: the cytoplasmic tail, transmembrane, extracellular stalk, and globular head. For henipavirus entry to occur, G interacts with the host cell receptor and undergoes receptor-induced conformational changes during which the stalk of G is exposed to F. The interaction between the head of F and G stalk domains leads to a rearrangement of the central region of the G stalk. This triggers F to initiate the fusion cascade, resulting in virus-cell membrane fusion, which is essential for viral entry or cell-cell membrane fusion. The G stalk is involved in maintaining an oligomeric structure, mediated by a distinct cluster of three cysteine residues. The roles of the stalk domain in other henipaviral glycoproteins, including MojV, remain unknown. Our main objective is to understand the role of the stalk domain within members of the Paramyxoviridae family during fusion activation and host cell entry. Overall, the results obtained from this research inform about the novel role G has in addition to receptor binding and fusion triggering in the fusion pore expansion step for NiV. Additionally, we discovered the MojV stalk cysteine residues are involved in oligomerization and modulate fusogenicity. By deepening our understanding of the mechanisms for paramyxovirus glycoprotein-driven membrane fusion, this research supports new methods to stop the infection and syncytia-associated pathogenesis and provide new targets for antivirals.2023-09-1