Probing Ebola’s deadly inflammatory effect

New research suggests that the massive and destructive inflammation that characterizes Ebola virus disease may be caused by the release of foreign proteins from infected cells.

Although Ebola is infamous for causing bleeding in some of its victims, doctors say the vast majority of deaths are the result of organ failure and shock brought on by the uncontrolled release of cytokines, compounds that cells use to communicate with one another and control immune response.

It remains somewhat of a mystery to scientists exactly why the immune system spins out of control when confronted by Ebola. It releases an excess of signaling compounds that dilate blood vessels and cause blood pressure to plummet, while immune cells inflict collateral damage on otherwise healthy cells during the fight.

The whole virus itself does not seem to trigger this frenzied response, they say.

In a paper published Thursday in Plos Pathogens, researchers at the Claude Bernard University of Lyon, in France, argued that glycoprotein shedding by infected cells may explain the immune system’s damaging response.

“These activities could be at the heart of the excessive and dysregulated inflammatory host reactions to infection and thus contribute to high virus pathogenicity,” wrote virologist and senior author Viktor Volchkov and his colleagues.

Glycoprotein GP “spikes” stud the surface of the string-shaped Ebola virus, and enable it to latch onto and enter host cells. Once inside, the virus hijacks the cell’s inner workings and begins to mass-produce components of itself that it assembles into whole viruses.

During this assembly process however, the host cell will shed, or release, some of the glycoproteins it produces. The glycoproteins will then enter the blood stream where they will encounter antibodies, as well as two key types of immune cells: macrophages and dendritic cells.

Until recently, researchers believed this release of proteins helped Ebola virus by acting as a decoy. Instead of attaching to the glycoprotein spikes of a fully assembled virus, and preventing it from entering a cell, many antibodies bound to the free-floating glycoproteins.

But Volchkov and his colleagues say that after studing viral components in the lab, they determined that Ebola glycoproteins caused immune cells to release cytokines, even when the whole virus wasn’t present.

While their hypothesis has yet to be proved in an infected animal or human, the authors hypothesize that the glycoproteins not only trigger the massive release of cytokines, but that they also lead to blood vessel permeability, the cause of hemorrhaging.

The authors said that it also appeared that immune cell response to glycoprotein could be muted by specific antibodies: anti-TLR4 antibodies.

“Overall, our data contribute to a better understanding of the way Ebola virus might provoke the excessive cytokine storm that appears to be detrimental to survival,” the authors wrote.

“It is intriguing to speculate that treatment with anti-TLR4 antibodies could be used to reduce the inflammatory reaction caused by shed glycoprotein.”

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