The paramyxoviruses, as a group, include many important human and animal pathogens, such as measles virus, the parainfluenza viruses, and the highly pathogenic, emerging, zoonotic henipaviruses: Hendra virus (HeV) and Nipah virus (NiV). HeV and NiV have a uniquely broad host tropism, infecting both animals and humans, causing a systemic and often fatal respiratory and/or neurological disease in at least 12 species across 6 orders of mammals. Both pose significant biothreats to both humans and economically important livestock. Henipaviruses, possess two membrane glycoproteins involved in virus entry, one mediates host cell receptor attachment (G glycoprotein) and the other is a Class I fusion (F) glycoprotein which facilitates fusion between the virion and host cell membranes. The G and F glycoproteins are also the major antigens of the virus-neutralizing antibody response in infected hosts and the targets of several antiviral strategies aimed at blocking virus entry. Conversely, the matrix (M) protein is an essential structural component of the virion and has been shown to play a central role in the morphogenesis and budding of progeny virus. Henipavirus M possess a unique ability to assemble and bud from cells in the absence of other viral proteins. Although extensively explored, many details of both the receptor binding and fusion triggering steps and the assembly and budding of progeny virions remain ill-defined for the henipaviruses and paramyxoviruses in general. Both the entry and exit of virus from the host cell are critical processes which also influence host tropism, and the henipaviruses are new virological systems in which to explore unanswered questions about these aspects of paramyxoviruses and negative-stranded enveloped RNA viruses in general. Studies on henipaviruses will further a detailed understanding of their cell biology and host cell interaction involved in virus entry and egress. Findings from these efforts will provide insight into the mechanisms that foster efficient cross-species transmission and also make them important pathogens, and will aid in the development of new antiviral strategies. Our efforts have focused on the henipavirus F and G glycoproteins, the receptor-binding and fusion steps, and the assembly and budding of virus-like-particles. Using the extensive data and systems we have developed in studying HeV and NiV, together with a new species of henipavirus, our objectives in the continuation of our program will be to further detail stages in the fusion and entry process and the assembly and budding of virus particles. Specifically, we will: 1) Characterize henipavirus matrix driven particle assembly in host cells including those from their bat hosts;2) Identify and characterize the domains involved in the interaction and fusion-triggering mechanism between the henipavirus F and G glycoproteins;3) Define and detail the interactions between the host cell ephrin receptors and henipavirus G glycoproteins.

Public Health Relevance

The paramyxoviruses, as a group, include many important human pathogens, such as measles virus, the parainfluenza viruses and the more recently identified and deadly zoonotic henipaviruses: Hendra virus and Nipah virus. Studies on these viruses will further a detailed understanding of henipavirus cell biology and their interaction wit host cells and provide insight into the mechanisms that make them important human and animal pathogens. Findings from these efforts will aid in the development of new therapeutics, intervention and vaccine strategies for the henipaviruses and paramyxoviruses in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI054715-06
Application #
8439710
Study Section
Virology - A Study Section (VIRA)
Program Officer
Cassetti, Cristina
Project Start
2003-04-01
Project End
2017-06-30
Budget Start
2013-07-17
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$355,116
Indirect Cost
$120,116
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Middleton, Deborah; Pallister, Jackie; Klein, Reuben et al. (2014) Hendra virus vaccine, a one health approach to protecting horse, human, and environmental health. Emerg Infect Dis 20:372-9
Mire, Chad E; Geisbert, Joan B; Agans, Krystle N et al. (2014) A recombinant Hendra virus G glycoprotein subunit vaccine protects nonhuman primates against Hendra virus challenge. J Virol 88:4624-31
Geisbert, Thomas W; Mire, Chad E; Geisbert, Joan B et al. (2014) Therapeutic treatment of Nipah virus infection in nonhuman primates with a neutralizing human monoclonal antibody. Sci Transl Med 6:242ra82
Bossart, Katharine N; Fusco, Deborah L; Broder, Christopher C (2013) Paramyxovirus entry. Adv Exp Med Biol 790:95-127
Broder, C C (2013) Passive immunization and active vaccination against Hendra and Nipah viruses. Dev Biol (Basel) 135:125-38
Xu, Kai; Rockx, Barry; Xie, Yihu et al. (2013) Crystal structure of the Hendra virus attachment G glycoprotein bound to a potent cross-reactive neutralizing human monoclonal antibody. PLoS Pathog 9:e1003684
Marsh, Glenn A; Virtue, Elena R; Smith, Ina et al. (2013) Recombinant Hendra viruses expressing a reporter gene retain pathogenicity in ferrets. Virol J 10:95
Colgrave, Michelle L; Snelling, Hayley J; Shiell, Brian J et al. (2012) Site occupancy and glycan compositional analysis of two soluble recombinant forms of the attachment glycoprotein of Hendra virus. Glycobiology 22:572-84
Steffen, Deborah L; Xu, Kai; Nikolov, Dimitar B et al. (2012) Henipavirus mediated membrane fusion, virus entry and targeted therapeutics. Viruses 4:280-308
Broder, Christopher C (2012) Henipavirus outbreaks to antivirals: the current status of potential therapeutics. Curr Opin Virol 2:176-87

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