The broad species tropisms and the ability to cause fatal disease in both animals and humans have distinguished the Henipaviruses', Hendra virus (HeV) and Nipah virus (NiV) from all other known paramyxoviruses. These viruses can be amplified and cause disease in animals and be transmitted to humans where infection is manifested as a severe respiratory illness and/or febrile encephalitis. They are now classified as biological safety level-4 (BSL-4) agents, and they possess several characteristics which make them highly adaptable for their use as bioterror agents as well. HeV appeared first in eastern Australia in 1994 and was transmitted to humans from infected horses; NiV first appeared in 1998-99 in peninsular Malaysia and was predominantly passed from infected pigs to humans, but several other animal species also became infected. Recently, both NiV and HeV continue to make their presence known, and in early 2004 two NiV outbreaks in Bangladesh have occurred totaling some 53 human cases of infection and another outbreak in 2005 in the same area claimed 12 more lives. HeV has reappeared in Australia in late 2004, with two cases of fatal infection in horses and one non-fatal human case. Significant observations in the recent NiV outbreaks have been made, including a higher incidence of acute respiratory distress syndrome, person-to-person transmission, higher case fatality rates (~70%), and no direct link to infected animals. Understanding their cell biology, how they mediate host cell infection and cross species transmission is now important and will aid our understanding of their pathogenic mechanisms and in the development of therapeutics, intervention, and vaccine strategies. Over the past five years my laboratory has studied the biochemical and functional properties of the viral glycoproteins and their fusogenic cellular tropisms, the budding of virus-like-particles, and most recently identified a receptor employed by both HeV and NiV (ephrin-B2). We have also produced candidate subunit vaccines as well as fusion inhibitors and human monoclonal antibody therapeutics. Using the data and systems we have developed, our objectives in the present proposal are to dissect apart certain details of the viral-mediated membrane fusion process and the assembly and budding steps of virus particles. Specifically, we will: i) Characterize virus particle assembly and identify the Henipavirus late domain element(s) in matrix, ii) Identify and define the domains involved in the interaction between the viral F and G glycoproteins; and iii) Characterize and define the interaction between ephrin-B2 and G; mapping their binding sites and exploring the consequences of receptor binding on the F and G interaction. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054715-03
Application #
7414041
Study Section
Virology - A Study Section (VIRA)
Program Officer
Cassetti, Cristina
Project Start
2006-05-01
Project End
2011-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
3
Fiscal Year
2008
Total Cost
$297,846
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Pickering, Brad S; Hardham, John M; Smith, Greg et al. (2016) Protection against henipaviruses in swine requires both, cell-mediated and humoral immune response. Vaccine 34:4777-86
Borisevich, Viktoriya; Lee, Benhur; Hickey, Andrew et al. (2016) Escape From Monoclonal Antibody Neutralization Affects Henipavirus Fitness In Vitro and In Vivo. J Infect Dis 213:448-55
Mire, Chad E; Satterfield, Benjamin A; Geisbert, Joan B et al. (2016) Pathogenic Differences between Nipah Virus Bangladesh and Malaysia Strains in Primates: Implications for Antibody Therapy. Sci Rep 6:30916
Broder, Christopher C; Weir, Dawn L; Reid, Peter A (2016) Hendra virus and Nipah virus animal vaccines. Vaccine 34:3525-34
Xu, Kai; Chan, Yee-Peng; Bradel-Tretheway, Birgit et al. (2015) Crystal Structure of the Pre-fusion Nipah Virus Fusion Glycoprotein Reveals a Novel Hexamer-of-Trimers Assembly. PLoS Pathog 11:e1005322
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
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
Baker, Kate S; Suu-Ire, Richard; Barr, Jennifer et al. (2014) Viral antibody dynamics in a chiropteran host. J Anim Ecol 83:415-28
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
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

Showing the most recent 10 out of 36 publications