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.
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.
|Smartt, Chelsea T; Shin, Dongyoung; Alto, Barry W (2017) Dengue serotype-specific immune response in Aedes aegypti and Aedes albopictus. Mem Inst Oswaldo Cruz 112:829-837|
|Purcell, Erin B; McKee, Robert W; Courson, David S et al. (2017) A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase. Infect Immun 85:|
|Ponnuswamy, Padmapriya; Joffre, Jeremie; Herbin, Olivier et al. (2017) Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells. Sci Rep 7:4111|
|Silva, Laurie A; Dermody, Terence S (2017) Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 127:737-749|
|Elong Ngono, Annie; Chen, Hui-Wen; Tang, William W et al. (2016) Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection. EBioMedicine 13:284-293|
|Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-?B activity and NF-?B-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76|
|Rowse, Michael; Qiu, Shihong; Tsao, Jun et al. (2016) Reduction of Influenza Virus Envelope's Fusogenicity by Viral Fusion Inhibitors. ACS Infect Dis 2:47-53|
|Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:|
|Bates, John T; Pickens, Jennifer A; Schuster, Jennifer E et al. (2016) Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates. Vaccine 34:950-6|
|Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-236|
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