One of the human body's first responses to a viral infection is to make and release signaling proteins, interferons, which amplify the immune system response to viruses.
Over time, many viruses have evolved to undermine interferons’ immune-boosting signal.
A paper published in Cell Host & Microbe describes a mechanism unique to the Ebola virus that defeats attempts by an interferon to block viral reproduction in infected cells. The study explains how the production by the virus of a protein called Ebola Viral Protein 24 (eVP24) stops the interferon-based signals from ramping up immune defenses. With the body's first response disabled, the virus mass produces itself and triggers the too-large immune response that damages organs and can become deadly as part of Ebola virus disease (EVD).
The study spotlights the part of the body's defense system that fights infection called innate immunity, the mix of proteins and cells that most quickly recognizes an invasion by a virus. This part of immunity keeps a virus from quickly reproducing inside cells. To trigger an effective, early response to viral infection, interferons must pass on their signal to other cells. This occurs through other messengers inside cells as part of interferon signaling pathways, with the last of these messengers turning on genes inside the nuclei of cells to drive the immune response.
The study determined the structure of eVP24 when bound to its cellular targets, transport proteins called karyopherins. Researchers used these structures to show how, in place of an interferon's natural downstream signal carrier phosphorylated STAT1, eVP24 docks into the karyopherins meant to escort STAT1 into cell nuclei, where it turns on interferon-targeted genes. By interfering at this stage, eVP24 cripples innate immunity to cause EVD.
Understanding exactly how the Ebola virus targets the interferon pathway could help guide drug development moving forward. It may be possible to find an antibody or molecule that interferes with eVP24, or that works around its competition with STAT1, such that treatment of patients with extra interferon might become useful against the virus.
Read the study.
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