The Paramyxoviridae family is comprised of globally prevalent human pathogens such as measles, mumps, human parainfluenza, and the deadly henipaviruses Nipah (NiV) and Hendra (HeV). NiV has a mortality rate in humans of ~75%, is a BSL-4 Category C priority pathogen in the NIAID Research Agenda and is listed by the WHO as likely to cause future pandemics, requiring ?urgent action.? NiV and HeV represent a rapidly growing genus with ~20 recently discovered henipaviruses; thus, it is possible that additional henipaviruses will emerge in the human population. For NiV animal-to-human and human-to-human transmission and the lack of approved vaccines or therapeutics, underscore the need for research and treatment development. The process of cell entry is key to infection of all viruses and provides targets for antiviral treatments. In our first funding period, we made significant progress in establishing novel concepts and tools to dissect the steps of the membrane fusion process. Thus, we are poised to build and expand upon this progress to mechanistically understand the membrane fusion process for the deadliest henipaviruses, with broader impact for the paramyxoviruses. Paramyxoviral entry into cells (viral-cell fusion) and the pathologic syncytia formation (cell-cell fusion) associated with infections, require membrane fusion, a process coordinated by two viral proteins: the attachment (HN, H, or G) and fusion (F) glycoproteins. How G/F interactions link cell receptor binding to F-triggering and later steps in the membrane fusion cascade remain critical knowledge gaps for the paramyxoviruses, including NiV and HeV. In our proposed studies, we will address these knowledge gaps and test the hypothesis that newly-discovered fusion-modulatory domains in NiV G and F modulate distinct specific early and late intermediates of the membrane fusion cascade. To test this hypothesis, we identified many useful G and F mutants, including mutants capable of receptor-binding but incapable of F-triggering, or capable of F-triggering but trapping the fusion cascade at post-F-triggering steps. These are exciting and highly-useful paramyxoviral phenotypes for teasing out the steps of the membrane fusion cascade. Further, our recent technical advances include: assays to measure the distinct early and late intermediates of membrane fusion, and tools to detect G and F conformational changes and interactions on viral particles in situ by flow virometry. Thus, for the first time, we have gathered the conceptual and technical advances needed to discern the individual membrane fusion intermediates and reveal mechanisms that govern henipaviral membrane fusion. We will use these tools to:
Aim 1. Determine how the NiV-G head and stalk domains modulate receptor-induced membrane fusion;
Aim 2. Determine how NiV-F modulates F-triggering and late membrane fusion steps;
and Aim 3. Determine how G/F interactions modulate membrane fusion and viral entry. Completion of our Aims will create a comprehensive mechanistic model for the henipaviral membrane fusion process leading to infection, with likely broader impact for the paramyxoviruses.

Public Health Relevance

The emerging henipaviruses are a growing genus of viruses that include the Nipah and Hendra viruses, which are deadly to humans. This study focuses on the viral glycoproteins, which coordinate their efforts to mediate entry of these viruses into host cells, and cell-cell fusion, a pathogenic event in viral infections. Our studies will provide a fundamental understanding of viral entry and cell-cell fusion and identify viral targets for the development of anti-viral therapeutic agents.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Park, Eun-Chung
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Cornell University
Schools of Veterinary Medicine
United States
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Zamora, J Lizbeth Reyes; Aguilar, Hector C (2018) Flow virometry as a tool to study viruses. Methods 134-135:87-97
Balmer, Bethany F; Getchell, Rodman G; Powers, Rachel L et al. (2018) Broad-spectrum antiviral JL122 blocks infection and inhibits transmission of aquatic rhabdoviruses. Virology 525:143-149
AlHajri, Salim M; Cunha, Cristina W; Nicola, Anthony V et al. (2017) Ovine Herpesvirus 2 Glycoproteins B, H, and L Are Sufficient for, and Viral Glycoprotein Ov8 Can Enhance, Cell-Cell Membrane Fusion. J Virol 91:
Johnston, Gunner P; Contreras, Erik M; Dabundo, Jeffrey et al. (2017) Cytoplasmic Motifs in the Nipah Virus Fusion Protein Modulate Virus Particle Assembly and Egress. J Virol 91:
Weed, Darin J; Pritchard, Suzanne M; Gonzalez, Floricel et al. (2017) Mildly Acidic pH Triggers an Irreversible Conformational Change in the Fusion Domain of Herpes Simplex Virus 1 Glycoprotein B and Inactivation of Viral Entry. J Virol 91:
Balmer, Bethany F; Powers, Rachel L; Zhang, Ting-Hu et al. (2017) Inhibition of an Aquatic Rhabdovirus Demonstrates Promise of a Broad-Spectrum Antiviral for Use in Aquaculture. J Virol 91:
Stone, Jacquelyn A; Vemulapati, Bhadra M; Bradel-Tretheway, Birgit et al. (2016) Multiple Strategies Reveal a Bidentate Interaction between the Nipah Virus Attachment and Fusion Glycoproteins. J Virol 90:10762-10773
Stone, Jacquelyn A; Nicola, Anthony V; Baum, Linda G et al. (2016) Multiple Novel Functions of Henipavirus O-glycans: The First O-glycan Functions Identified in the Paramyxovirus Family. PLoS Pathog 12:e1005445
Aguilar, Hector C; Henderson, Bryce A; Zamora, J Lizbeth et al. (2016) Paramyxovirus Glycoproteins and the Membrane Fusion Process. Curr Clin Microbiol Rep 3:142-154
Plattet, Philippe; Alves, Lisa; Herren, Michael et al. (2016) Measles Virus Fusion Protein: Structure, Function and Inhibition. Viruses 8:112

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