Henipaviruses show increasing impact as causes of central nervous system illness in the human community. We propose to apply our understanding of paramyxovirus entry to the development of new strategies for inhibiting infection that will apply to newly emerging paramyxoviruses. The first step in paramyxovirus infection is the binding of the receptor-binding protein (G for Hendra and Nipah viruses;HeV/NiV) to receptor on the cell's surface (EFNB2 for HeV/NiV). Receptor engagement activates the viral fusion proteins (F) to fusion-ready conformation, and F then inserts into the target cell membrane, fusing the viral envelope with the cell's membrane and allowing viral entry. In a novel therapeutic approach, we will identify compounds that induce F to trigger prematurely, inactivating the viruses before they can enter the target cells. 1. Proof of concept for new antiviral platform: Paramyxovirus receptor mimics induce premature triggering of F distant from the target cell.
This aim will test the hypothesis that if G-receptor interaction can be mimicked before an infectious viral particle binds to the cell surface, F can be induced to be triggered prematurely and be inactivated. We will assess whether soluble receptor-mimicking molecules inhibit multicycle replication in relevant tissue models for human vascular endothelium and for human CMS parenchymal cells. Support of this aim includes evidence for
Hendra and Nipah viruses are urgent concerns for public health due to their transmissible nature and increasing impact on acute and chronic central nervous system disease. This research proposal will lead to a new antiviral strategy that will apply to henipaviruses, existing and emerging paramyxoviruses as well as other enveloped viruses. The results will be highly relevant in light of the importance of paramyxoviruses to human health and the potential broad applicability of the new platform to these and other serious pathogens.
|Charles, Jermilia; Firth, Andrew E; LoroÃ±o-Pino, Maria A et al. (2016) Merida virus, a putative novel rhabdovirus discovered in Culex and Ochlerotatus spp. mosquitoes in the Yucatan Peninsula of Mexico. J Gen Virol 97:977-87|
|Pham, Alissa M; Santa Maria, Felicia Gilfoy; Lahiri, Tanaya et al. (2016) PKR Transduces MDA5-Dependent Signals for Type I IFN Induction. PLoS Pathog 12:e1005489|
|Song, Jeongmin; Wilhelm, Cara L; Wangdi, Tamding et al. (2016) Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell 164:827-8|
|Li, Melody M H; Bozzacco, Leonia; Hoffmann, Hans-Heinrich et al. (2016) Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion. J Exp Med 213:2931-2947|
|Moser, Lindsey A; Lim, Pei-Yin; Styer, Linda M et al. (2016) Parameters of Mosquito-Enhanced West Nile Virus Infection. J Virol 90:292-9|
|Basu, Debaleena; Kahn, Jennifer N; Li, Xiao-Ping et al. (2016) Conserved Arginines at the P-Protein Stalk Binding Site and the Active Site Are Critical for Ribosome Interactions of Shiga Toxins but Do Not Contribute to Differences in the Affinity of the A1 Subunits for the Ribosome. Infect Immun 84:3290-3301|
|Steyer, Andrej; JevÅ¡nik, Monika; Petrovec, Miroslav et al. (2016) Narrowing of the Diagnostic Gap of Acute Gastroenteritis in Children 0-6 Years of Age Using a Combination of Classical and Molecular Techniques, Delivers Challenges in Syndromic Approach Diagnostics. Pediatr Infect Dis J 35:e262-70|
|Uhde, Melanie; Ajamian, Mary; Li, Xueting et al. (2016) Expression of C-Reactive Protein and Serum Amyloid A in Early to Late Manifestations of Lyme Disease. Clin Infect Dis 63:1399-1404|
|Jacek, Elzbieta; Tang, Kevin S; Komorowski, Lars et al. (2016) Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease. J Immunol 196:1036-43|
|Aguilar, Jorge L; Varshney, Avanish K; Pechuan, Ximo et al. (2016) Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus. Virulence :1-10|
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