Scripps Research Joint Appointments

Professor, Department of Integrative Structural and Computational Biology
Faculty, Kellogg School of Science and Technology

Research Focus

Structural Studies of Viral Hemorrhagic Fever Pathogenesis

In my laboratory, we are crystallizing proteins that play key roles in the pathogenesis and lethality of hemorrhagic fever viruses. The resulting crystal structures of these proteins will provide information seminal to the design of vaccines and inhibitors against the viruses as they exist naturally, and will also provide structural templates that would permit us to anticipate and rapidly respond to newly emerging and man-made versions of the virus and viral proteins.

Ebola Virus
There have been at least 10 recognized outbreaks of the Ebola virus, each with a 50-90% human case fatality. To date there are no available vaccines or treatments. An unusual feature of the viral genome is its ability to encode two different glycoproteins, sGP and GP, from the same gene. sGP and GP share 295 amino acids of N-terminal sequence, but a transcriptional editing event causes them to have different C-terminal sequences. The different C termini result in unique patterns of disulfide bonding, structures, and roles in pathogenesis. sGP forms an antiparallel dimer and is secreted in large quantities from infected cells. GP forms a parallel trimer on the viral surface, and functions in viral attachment, fusion, and tropism. GP may also cause some of the hemorrhagic symptoms seen in Ebola virus infection. Comparative structural analysis of sGP and GP should explain how two structures arise from the same sequence, and provide templates to guide the design of vaccines that elicit antibodies which target the virus rather than the secreted proteins. Additional crystal structures of these proteins in complex with human antibodies derived from survivors of Ebola virus infection will assist vaccine design.

An additional crystallographic target is the VP35 protein, a required component of the Ebola viral capsid and transcription complex. VP35 also blocks type I interferon activation of immunomodulatory genes and may play a significant role in Ebola virus suppression of the host immune system. Hence, structural analysis of the VP35 protein may provide insights into viral replication and type I interferon suppression and will provide the structural basis for the design of anti-viral compounds and attenuated viral strains.

Dengue Virus
Dengue virus is a mosquito-borne flavivirus that causes up to 100 million infections per year. Infection with dengue virus results in either Dengue Fever or the much more severe disease Dengue Hemorrhagic Fever (DHF). Development of DHF usually occurs upon secondary infection with a different viral subtype, or in infants born to dengue-immune mothers, suggesting that in some circumstances antibodies against the virus may actually enhance disease severity. Potential antibody-mediated enhancement of dengue virus infection is a major concern in the testing and use of vaccines against dengue. Crystal structures of human antibodies in complex with dengue antigens will provide a structural basis for understanding this phenomenon and will offer novel templates for design of safe vaccines.

Education

Ph.D., Macromolecular and Cellular Structure and Chemistry, The Scripps Research Institute, 2000

Awards & Professional Activities

Burroughs Wellcome Career Award in the Biomedical Sciences
New Initiatives Award in Global Infectious Disease, The Ellison Medical Foundation
Fellow, Universitywide AIDS Research Program
Surhain Sidhu Award, Pittsburgh Diffraction Society

Selected References

Zhang APP, Halfmann P, Bornholdt ZA, Abelson DM, Kawaoka Y, and Saphire EO. (2012). Crystal
structures of the ebolavirus interferon antagonist VP24 reveal a pyramidal fold and sites required for virulence. PLOS Pathogens, 8:e1002550. 

Hastie KM,  Liu T,  King LB, Zandonatti MA,  Ngo N,Woods-Jr VL, de la Torre JC, and Saphire EO. (2011) Crystal Structure of the Lassa Virus Nucleoprotein-RNA Complex Reveals a Gating Mechanism for RNA binding. Proc. Natl. Acad. Sci., USA, 108:19365-70.

Dias JM, Keuhne A, Abelson DM, Bale S, Wong A, Halfmann P, Muhammad MA, Fusco ML, Kawaoka Y, Chandran K, Dye JM,  and Saphire EO. (2011) A shared structural solution for neutralizing ebolaviruses. Nature Struct. Mol. Biol.,18:1424-7.

Hastie KM, Kimberlin CR, Zandonatti MA, Macrae IJ & Saphire EO. (2011) Structure of the Lassa virus nucleoprotein reveals a dsRNA-specific 3' to 5' exonuclease activity essential for immune suppression. Proceedings of the National Academy of Sciences USA 108, 2396-401.

Kimberlin CR, Bornholdt ZA, Li S, Woods VL Jr, MacRae IJ, Saphire EO. (2010) Ebolavirus VP35 uses a bimodal strategy to bind dsRNA for innate immune suppression. Proceedings of the National Academy of Sciences USA 107, 314-9.

Lee JE, Fusco ML, Hessell AJ, Oswald WB, Burton DR, Saphire EO. (2008) Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor. Nature 474, 177-183.