Alphaviruses are a group of over 25 mosquito transmitted single-stranded RNA viruses that cause severe human disease on all continents except Antarctica. Three of these are Category B select agents (Venezuelan, Eastern and Western Encephalitis viruses), and at least one (VEE) has been weaponized in the past by both the U.S. and the Soviet Union. The most recent large VEE epidemic occurred in 1995 with massive equine mortality and over 100,000 human cases with an approximately 1% case mortality rate. Chikungunya (CHIK) is a Category C agent and the cause of endemic severe febrile illness in Africa characterized by acute and debilitating joint pain which can persist for months after viral clearance. The virus has emerged as an epidemic of over 2 million cases currently engulfing the Indian subcontinent and Indonesia, and through an infected traveler, it now has spread to Italy. There are neither therapeutics nor licensed human vaccines for any alphavirus. We propose 1) to examine the pathogenesis of CHIK in a recently established mouse model that recapitulates its human clinical manifestations, and 2) to produce a candidate vaccine for this important emerging infection. Moreover, we will extend published results on cross-protective alphavirus B-cell epitopes and recent observations of T-cell mediated protection against alphavirus challenge to design a vaccine broadly effective against multiple members of the alphavirus genus. This practical approach conforms to the NIH mandate of designing vaccines and therapeutics effective against multiple agents.

Public Health Relevance

The alphaviruses include 3 viruses present in the Americas that are considered potential agents of bioterrorism. Another has emerged from Africa and is currently causing a raging epidemic in Asia involving over 2 million documented cases to date. Additional cases have arisen in Italy, illustrating the enormous potential for global spread. The proposed research will examine the pathogenesis of these viruses and will design and test a vaccine. Currently, there are no licensed therapeutics or vaccines for any alphavirus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057157-10
Application #
8375894
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$203,689
Indirect Cost
$54,684
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Dethoff, Elizabeth A; Boerneke, Mark A; Gokhale, Nandan S et al. (2018) Pervasive tertiary structure in the dengue virus RNA genome. Proc Natl Acad Sci U S A 115:11513-11518
Graham, Rachel L; Deming, Damon J; Deming, Meagan E et al. (2018) Evaluation of a recombination-resistant coronavirus as a broadly applicable, rapidly implementable vaccine platform. Commun Biol 1:179
Qi, Xiaoxuan; Wang, Wenjian; Dong, Haohao et al. (2018) Expression and X-Ray Structural Determination of the Nucleoprotein of Lassa Fever Virus. Methods Mol Biol 1604:179-188
Kocher, Jacob F; Lindesmith, Lisa C; Debbink, Kari et al. (2018) Bat Caliciviruses and Human Noroviruses Are Antigenically Similar and Have Overlapping Histo-Blood Group Antigen Binding Profiles. MBio 9:
Dhanwani, Rekha; Huang, Qinfeng; Lan, Shuiyun et al. (2018) Establishment of Bisegmented and Trisegmented Reverse Genetics Systems to Generate Recombinant Pichindé Viruses. Methods Mol Biol 1604:247-253
Shao, Junjie; Liu, Xiaoying; Liang, Yuying et al. (2018) Assays to Assess Arenaviral Glycoprotein Function. Methods Mol Biol 1604:169-178
Huang, Qinfeng; Shao, Junjie; Liang, Yuying et al. (2018) Assays to Demonstrate the Roles of Arenaviral Nucleoproteins (NPs) in Viral RNA Synthesis and in Suppressing Type I Interferon. Methods Mol Biol 1604:189-200
Gunn, Bronwyn M; Jones, Jennifer E; Shabman, Reed S et al. (2018) Ross River virus envelope glycans contribute to disease through activation of the host complement system. Virology 515:250-260
Shao, Junjie; Liang, Yuying; Ly, Hinh (2018) Roles of Arenavirus Z Protein in Mediating Virion Budding, Viral Transcription-Inhibition and Interferon-Beta Suppression. Methods Mol Biol 1604:217-227
Wirawan, Melissa; Fibriansah, Guntur; Marzinek, Jan K et al. (2018) Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody. Structure :

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