In the previous period of funding by the PSW RCE, we have studied the entry pathways used by the New World clade B arenaviruses. This sub-group of the Arenavirus family contains 5 emerging human pathogens, capable of causing severe hemorrhagic fevers. Since clade B contains both pathogenic and non-pathogenic members, it has proved to be a powerful system with which to elucidate the determinants of human pathogenicity. We have identified several key differences between the two groups, including the fact that human transferrin receptor 1 (TfR1) is only used as a cellular receptor by the human pathogens. This suggests that the virus glycoprotein (GP)-TfR1 interaction is likely of great importance for the ability of clade B arenaviruses to infect humans. This finding has several implications: (1) it is likely that the interaction between GP and TfR1 will represent a good therapeutic target, (2) the ability of any newly discovered clade B arenaviruses to use TfR1 may be a good predictor of human pathogenic potential, and (3) targeting antiviral drugs to cells that express TfR1 may promote the delivery of therapeutics to the same cells that the viruses preferentially infect. TfR1 is not the only cellular receptor to be used by the arenaviruses. Previously, a-dystroglycan was shown to play an important role in the entry pathway of several arenaviruses, including Old World and New World clade C viruses, and our own data indicates that at least 2 other unknown receptors are used by this family. Such receptor choice flexibility within the arenaviruses suggests that these viruses could continue to evolve in directions that would allow other species-jumping events into humans. Our goals for the next 5 years of funding are to continue to build a more complete picture of receptor use by the New World arenaviruses, and to exploit this information in the development of anti-arenaviral therapeutics, including TfR1-targeted siRNA nanoparticles. Simultaneously, we will develop better BSL-2 animal models with which to evaluate the effectiveness of these reagents.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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University of California Irvine
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Torres, Rodrigo; Lan, Benson; Latif, Yama et al. (2014) Structural snapshots along the reaction pathway of Yersinia pestis RipA, a putative butyryl-CoA transferase. Acta Crystallogr D Biol Crystallogr 70:1074-85
Houghton, Raymond L; Reed, Dana E; Hubbard, Mark A et al. (2014) Development of a prototype lateral flow immunoassay (LFI) for the rapid diagnosis of melioidosis. PLoS Negl Trop Dis 8:e2727
Strotmeier, Jasmin; Mahrhold, Stefan; Krez, Nadja et al. (2014) Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A. FEBS Lett 588:1087-93
Koellhoffer, Jayne F; Dai, Zhou; Malashkevich, Vladimir N et al. (2014) Structural characterization of the glycoprotein GP2 core domain from the CAS virus, a novel arenavirus-like species. J Mol Biol 426:1452-68
Bennett, Shannon N; Gu, Se Hun; Kang, Hae Ji et al. (2014) Reconstructing the evolutionary origins and phylogeography of hantaviruses. Trends Microbiol 22:473-82
Burtnick, Mary N; Brett, Paul J; DeShazer, David (2014) Proteomic analysis of the Burkholderia pseudomallei type II secretome reveals hydrolytic enzymes, novel proteins, and the deubiquitinase TssM. Infect Immun 82:3214-26
Koskiniemi, Sanna; Garza-Sánchez, Fernando; Sandegren, Linus et al. (2014) Selection of orphan Rhs toxin expression in evolved Salmonella enterica serovar Typhimurium. PLoS Genet 10:e1004255
Sabouri, Amir H; Marcondes, Maria Cecilia Garibaldi; Flynn, Claudia et al. (2014) TLR signaling controls lethal encephalitis in WNV-infected brain. Brain Res 1574:84-95
Vigant, Frederic; Hollmann, Axel; Lee, Jihye et al. (2014) The rigid amphipathic fusion inhibitor dUY11 acts through photosensitization of viruses. J Virol 88:1849-53
Relman, David A (2014) "Inconvenient truths" in the pursuit of scientific knowledge and public health. J Infect Dis 209:170-2

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