Secret Weapon of Infamous Ebola Virus Pinpointed and Defused
Using genetic mutations of the Ebola virus, researchers made a big step towards pinpointing and defusing the mechanism behind one of the virus' most dangerous attributes: its ability to disarm the adaptive immune system.
University of Texas Medical Branch at Galveston scientists located the positions in the genetic code of the Ebola virus that generates key proteins enabling the virus to short-circuit the immune system. With these special proteins, Ebola is able to prevent the full development of human dendritic cells that would otherwise trigger an immune response to the virus.
"Dendritic cells typically undergo a process called 'maturation' when they're infected by a virus -- they change shape and present antigens on their surface that tell T-cells to attack that particular virus, thus generating an adaptive immune response," said UTMB professor Alexander Bukreyev, senior author of a paper on the discovery now online in the Journal of Virology. "But Ebola prevents dendritic-cell maturation and produces a severe infection without an effective adaptive immune response. We found that its ability to do this depends on several specific regions of two different proteins."
Bukreyev's research group made the discovery after a series of procedures that started with a clone of the Ebola Zaire virus strain. Working under maximum-containment conditions in a biosafety level 4 facility in UTMB's Galveston National Laboratory, the team introduced mutations into the virus' genetic code at four locations thought to generate proteins that affected immune response.
"We saw two very interesting things," Bukreyev said. "First, that these mutations restore maturation of dendritic cells very effectively, and second, that a mutation in even one of these genetic domains makes the virus unable to suppress maturation. That means that the virus needs multiple combined effects in order to undermine the immune system in this way."
Ebola's ability to evade the human immune response is one of the factors that accounts for its high mortality rate -- up to 90 percent in humans -- and the notoriety that it gained after its first appearance in Zaire in 1976, in an outbreak that killed 280 people. Zaire -- now the Democratic Republic of the Congo -- is the home country of Ndongala Lubaki, lead author on the paper and a postdoctoral fellow at UTMB.
N. M. Lubaki, P. Ilinykh, C. Pietzsch, B. Tigabu, A. N. Freiberg, R. A. Koup, A. Bukreyev. The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains. Journal of Virology, 2013; DOI: 10.1128/JVI.03316-12