July 18, 2001 The folate receptor, a protein expressed on the surface of many human cells, could be capable of transporting much more into the cell than just folic acid-the B vitamin involved in normal bodily functions and cell development. In fact, the Ebola and Marburg viruses apparently can hitch a ride on the receptor and find their way into a cell as the first step in the viral infection cycle, researchers at the Gladstone Institute of Virology and Immunology and the University of California, San Francisco are showing for the first time.
Once these deadly viruses enter the cell, they begin to replicate, spread throughout the body, and cause the characteristic hemorrhagic fevers that lead to death in up to 90 percent of people infected. Current treatments are largely ineffective. Although for the most part Ebola and Marburg have exacted their human toll in periodic outbreaks in Africa, incidental transmission to Europe and the United States has also occurred.
In the study, the researchers used cells known to be naturally resistant to infection. Genes from cells that are susceptible to infection were randomly inserted into the resistant cells. When these cells were exposed to either the Ebola or Marburg viruses, only those with the gene encoding the folate receptor were infected.
Published in the July 13 issue of the journal Cell, the study advances the understanding of the Ebola and Marburg life cycles of which little is known. Entering the cell is a first and essential step in the viruses' move to replicate itself. Finding a molecule to inhibit the viruses from binding to the folate receptor could form the basis for a treatment, said senior author Mark A. Goldsmith, MD, PhD, associate investigator at Gladstone and UCSF associate professor of medicine.
"Targeting the virus in the first step in the replication cycle is an intellectually compelling idea," Goldsmith said. "It could stop the virus dead in its tracks before it has an opportunity to multiply and seek new cells to infect. A similar understanding of cell entry pathways used by another deadly virus, the human immunodeficiency virus (HIV), has been an important foundation for emerging new therapies for AIDS."
In one experiment, the researchers were able to inhibit both the Ebola and Marburg viruses from infecting a cell when they exposed the cells to high concentrations of folic acid. Exposing cells to an antibody specifically designed to bind to the folate receptor or to a "decoy" form of the folate receptor also inhibited the viruses.
Goldsmith emphasized that much more study needs to be done before folate or other binding proteins can be used as treatments. Other molecules could be found that would do a better job of blocking entry, he said. What also remains to be answered is whether the viruses can use other receptors to gain entry into the cell. Goldsmith and colleagues strongly suspect that there are such alternate pathways.
Studying the Ebola and Marburg viruses was possible through the use of pseudotype viruses-viruses that can infect but can't replicate, said lead author Stephen Chan, PhD, former graduate student at Gladstone and UCSF medical student. Traditionally, study of the two viruses has been hampered by the need for a maximum safety facility, of which there are only a few in the world. Pseudotype viruses are much safer to handle, which makes such research studies possible without the use of high-level containment facilities.
Chan and Goldsmith are one of only a few research teams to publish studies using pseudotype viruses for Ebola and Marburg. The ones developed by Chan use selected components of HIV to generate disabled viruses with some special features that make them useful for genetic experiments. Colleagues at the United States Army Medical Research Institute for Infectious Diseases confirmed the study's key findings by experiments using live, natural viruses in a maximum safety facility.
Co-investigators of the study include Cyril J. Empig, PhD, postdoctoral fellow, Frank J. Welte, graduate student, Roberto F. Speck, MD, former postdoctoral fellow and now assistant professor of medicine at the University Hospital in Zurich, and Jason F. Kreisberg, graduate student, all of Gladstone; and Alan Schmaljohn, PhD, United States Army Medical Research Institute for Infectious Diseases chief of viral pathogenesis and immunology in the virology division.
The study was funded by the J. David Gladstone Institutes. Chan was supported by the National Institutes of Health Medical Scientist Training Program and the UCSF Biomedical Sciences Program.
The Gladstone Institute of Virology and Immunology is one of three research institutes that comprise The J. David Gladstone Institutes, a private biomedical research institution affiliated with UCSF. The institution is named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing personal interest in medical education and research.
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