 |
 |
Community
X-Sci 2004 Speaker
Erica Ollmann Saphire, Ph.D.
Assistant Professor
Department of Immunology
Education
Ph.D., The Scripps Research Institute, 2000 Awards & 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
Awards & Activities, Publications
Click here to
view a list of selected publications with links and Curriculum Vitae.
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.
|
|
