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Oscar Negrete, Ph.D.

Virologist

Research Summary

Dr. Negrete's research interests lie in characterizing the entry mechanisms of highly pathogenic zoonotic viruses. Nipah virus (NiV) is an emerging virus with one of the highest mortality rates in humans (˜ 75%) and a broad host range that extends to livestock. Rift Valley fever virus (RVFV) is a mosquito–borne pathogen that primarily affects livestock, but can also cause lethal hemorrhagic fever and encephalitis in humans. Having discovered the cell receptors required for Nipah virus entry into cells, his research continues to focus on identifying new determinants of viral entry for NiV and RVFV. A current topic of study includes using genome–wide RNA interference screening to identify novel host factors and pathways involved in RVFV entry. His research uses a broad spectrum of biochemical, cellular, molecular biology, and immunological techniques to dissect membrane fusion and entry mechanisms. Viral entry studies are anticipated to assist in the formulation of new therapeutic, vaccine and diagnostics for Nipah virus and Rift valley fever virus.

Appointments

2013 – present Senior Member of Technical Staff, Sandia National Laboratories, Livermore, California
2008 – 2012 Postdoctoral Appointee, Sandia National Laboratories, Livermore, California

Education

2007 PhD, Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (Nipah virus entry with Benhur Lee, M.D.)

Current Research Projects at Sandia

Project 1

Developing microfluidic high-throughput screening (HTS) technologies for RNAi studies of virus–host interactions

RNAi technology has recently emerged as a powerful tool to investigate host proteins involved in virus replication on a genome–wide level. However, the interface of the high-throughput equipment necessary to perform such large RNAi screenings becomes problematic when assaying viral pathogens requiring high-level biocontainment. The accessibility of genome–wide RNAi technology is also limited by capital–expense and reagent costs. Therefore, to circumvent issues with current RNAi screening methods, we will develop a microfluidic–based device that combines cellular microarray, cell electroporation, and microfluidic channels to efficiently introduction RNAi libraries into primary cells within a portable and cost-effective platform.

Publications:

Harmon B, Kozina C, Maar D, Carpenter T, Branda C, Negrete OA, Carson B. (2013). Identification of Critical Amino Acids within the Nucleoprotein of Tacaribe virus important for anti-interferon activity. Journal of Biological Chemistry. 288(12):8702-8711.

Schudel B, Harmon B, Abhyankar V, Pruitt B, Negrete OA, Singh A. (2013) Microfluidic platforms for RNA interference screening of virus–host interactions. Lab on a Chip. 13:811-817.

Harmon B, Schudel B, Maar D, Kozina C, Ikegami T, Tseng C, Negrete OA. (2012) Rift Valley Fever virus strain MP–12 enters mammalian host cells via caveolae mediated endocytosis. Journal of Virology. 86(23):12954-12970.

Maar D, Harmon B, Chu D, Shultz B, Aguilar HC, Lee B, Negrete OA. (2012) Cysteines in the stalk domain of the Nipah virus G glycoprotein are located in a distinct subdomain critical for fusion activation. Journal of Virology. 86(12):6632-42.

Wolf, MC, AN Freiberg, T Zhang, ZA Ataman, J Li, PW Hong, AC Aguilar, A Grock, AN Honko, J Johnson, M Porotto, R Damoiseaux, J Miller, OA Negrete, P Krogstad, A Moscona, LE Hensley, SP Whelan, MR Holbrook, ME Jung, B Lee. (in press). A broad–spectrum antiviral targeting enveloped viruses. Proceedings of the National Academy of Sciences.

Aguilar, HC, ZA Ataman, V Aspericueta, AQ Fang, M Stroud, OA Negrete, RA Kammerer, B Lee. (2009). Receptor-induced activation of the Nipah virus attachment glycoprotein (G) that triggers the fusion glycoprotein (F). Journal of Biological Chemistry 284:1628.

Negrete, OA, D Chu, HC Aguilar, B Lee. (2007). Single amino acid changes in the Nipah and Hendra virus attachment glycoprotein distinguishes ephrinB2 from ephrinB3 usage. Journal of Virology 81:10804.

Negrete, OA*, MC Wolf *, B Lee. (2007). The pathobiology of henipavirus entry: Insights into therapeutic strategies. Future Virology 2:267. *Contributed equally.

Aguilar, HC, KA Matreyek, CM Filone, ST Hashimi, EL Levroney, OA Negrete, A Bertolotti–Ciarlet, DY Choi, I McHardy, JA Fulcher, SV Su, MC Wolf, L Kohatsu, LG Baum, B Lee. (2006). N-glycans on Nipah virus fusion protein protect against neutralization but reduce membrane fusion and viral entry. Journal of Virology 80:4878.

Negrete, OA, MC Wolf, HC Aguilar, S Enterlein, W Wang, E Muhlberger, SV Su, A Bertolotti–Ciarlet, R Flick, B Lee. (2006). Two key residues in ephrinB3 are critical for its use as an alternative receptor for Nipah virus. PLoS Pathogenesis 2:e7.

Negrete, OA, EL Levroney, HC Aguilar, A Bertolotti–Ciarlet, R Nazarian, S Tajyar, B Lee. (2005). EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. Nature 436:401.

Su, SV, P Hong, S Baik, OA Negrete, KB Gurney, B Lee. (2004). DC–SIGN binds to HIV–1 glycoprotein 120 in a distinct but overlapping fashion compared with ICAM–2 and ICAM–3. Journal of Biological Chemistry 279:19122.

Patents:

Lee, B, OA Negrete. Henipavirus receptor and uses thereof. Patent Application WO/2007/005244. June16, 2006.

Perroud T, Renzi R, Negrete O, Claudnic MR. A Microelectroporation device for genomic screening. U.S. Patent Application 13/173,180. June 31, 2011.

Ashely C, Brinker CJ, Carnes EC, Fekrazad MH, Felton LA, Negrete O, Padilla DP, Wilkinson BS, Wilkinson DC, Willman CL. Porous nanoparticle–supported lipid bilayers (protocells) for targeted delivery including transdermal delivery of cargo and methods thereof. International Patent Application PCT/US12/60072. October 12, 2012.

Contact Information:

Dr. Oscar A. Negrete
Biotechnology and Bioengineering Department
Sandia National Laboratories
PO Box 969, MS 9292
Livermore, CA 94551-0969

onegret@sandia.gov
phone: 925-294-6359
fax: 925-294-3020