Some survivors of ebolavirus outbreaks make antibodies that can largely neutralize these viruses – and now scientists at Scripps Research have shown how these antibodies can deactivate viruses so effectively. The information can be useful in developing effective therapies.
The Ebolavirus virus is a family of often fatal viruses that includes the Ebola virus and many lesser-known viruses such as Bundibugyo virus, Sudan virus, and Reston virus.
Structural biologists at Scripps Research used electron microscopy techniques to visualize a set of antibodies that target a key site in these viruses called “glycan cap.” Their research has shown that antibodies work against ebolaviruses using the same three mechanisms to prevent the virus from infecting host cells.
The research, published in Cell reports, is a step towards creating an antibody therapy that will be helpful against a wide range of ebolaviruses.
“We now understand the molecular basis of the ability of these antibodies to neutralize ebolviruses with broad reactivity against different viral species,” says study lead author Daniel Murin, PhD, a scientist in Andrew Ward’s lab, PhD.
Ward, a professor in the integrative and computational structural biology department at Scripps Research, says he hopes the work will help develop a “cocktail” of therapeutic antibodies that can save lives by treating many forms of the Ebola virus.
“The goal is to provide doctors in Ebola-prone areas with their best weapon against these deadly epidemics,” says Ward. “The knowledge we have gained from our structural studies of the virus shows how this can be possible.”
Ebola still emerging
The first known ebolavirus, now referred to as Zaire ebolavirus or simply Ebola virus, was identified in 1976, named after the site of an outbreak that year near the Ebola River in what was then Zaire and is today. hui the Democratic Republic of the Congo.
Other species have since been added to this virus family, including Sudan Ebolavirus and Bundibugyo Ebolavirus. Ebola viruses colonize African bats, often cause disease in chimpanzees and other non-human primates, and trigger epidemics in humans every few years on average. People who are infected develop a fatal hemorrhagic syndrome in about half of untreated cases.
Ebola vaccines have been developed recently but have not yet been widely used. And although antibody-based treatments have also been developed, none have been shown to be effective against a wide range of ebolavirus species.
Nevertheless, studies carried out in recent years have shown that some survivors of Ebola infections carry antibodies which, in laboratory tests, can neutralize several species of Ebolavirus. A surprisingly high proportion of these largely neutralizing antibodies target the glycan hood, a sugar-coated site on a rod-shaped protein – called a glycoprotein – that allows Ebola viruses to enter host cells.
In the new study, Murin and Ward, along with their colleagues at Vanderbilt University’s James Crowe Lab, where the antibodies were isolated, used electron microscopy to analyze a set of antibodies targeting the cap of glycans from survivors. various ebolaviruses. Their goal was to better understand how these antibodies target the virus so effectively.
Three ways to beat the virus
Their analysis suggested that the most widely effective of these antibodies targeting the glycan cap reached the same vulnerable site on the glycan cap, allowing them to counteract viral infectivity in three ways.
First, the antibody displaces a long viral structure near the glycan cap in a way that destabilizes the entire structure of the viral glycoprotein, sometimes causing it to collapse.
Second, the glycan cap antibody – when it binds to its target site – can block a key event in the infection process, in which an enzyme called cathepsin cleaves the glycan cap. Blocking this cleavage event blocks the ability of the glycoprotein to enter host cells.
Finally, the glycan cap antibody, by moving the loose structure near the glycan cap, allows another type of neutralizing antibody to bind to a separate vulnerable site on the virus. Thus, a glycan cap antibody can “synergize” with another antibody to hit the virus significantly harder than either antibody alone.
Scientists have also determined the key genetic elements that allow glycan-cap antibodies to thwart ebolaviruses in all three of these ways.
Now that they’ve shed some light on how these largely neutralizing antibodies work, Ward, Murin, and colleagues are testing them as part of a cocktail of next-generation antibodies that they hope will be able to treat Zaire’s ebolaviruses. , Sudan and Bundibugyo.