Ebola virus, part of the filovirus family, Filoviradae, causes rapid lethal hemorrhagic fever, and fatality rates up to 90%. From December 2013 to May 2015, Ebola virus infected more than 25,000 people and led to over 10,000 related deaths in West Africa. The recent outbreak has served to highlight the need for scientists to discover and develop vaccines and therapies for the treatment of Ebola.
In order to prevent a similar outbreak, scientists must first understand how the virus infects humans, or more specifically, how the virus enters and infects human cells. A group of researchers from China have pinpointed this exact mechanism. Gao and colleagues investigated the mechanism by which Ebola infects humans and determined the structure of the key proteins involved in Ebola infection.
In order to grasp how Ebola enters a cell, it is important to understand endocytocis, or the process by which a cell internalizes outside material. For instance, when a country needs a good that it does not produce, the country can import that good via ship from another country. Once the ship reaches the port, the goods get processed and sent on to their final destination. Similarly, a cell often has to rely on nutrients available in its external environment. The cell gets these nutrients by internalizing them into vesicles (analogous to the ship). Once inside the cell, these vesicles are processed and the nutrients are delivered to where they are needed. When Ebola infects a cell, it too is internalized into a vesicle. Before it reaches the “port”, where it would be degraded, the virus escapes the vesicle and goes on to infect surrounding cells.
The exact mechanism in which Ebola escapes the vesicle, however, is unknown. Researchers are investigating different steps in the replication of the virus to determine where roadblocks may be placed to prevent the virus from replicating and infecting the host. Gao and colleagues investigated the interaction between the virus and the vesicle at the point of viral release. Previous research has shown that Ebola requires one host protein to invade the cell, called Neimann-Pick C1 (NPC1), which is found on the host vesicle. Without this protein, the virus would not be able to penetrate the cell. Thus NPC1 represents an ideal target for antiviral intervention. Ebola uses an activated glycoprotein (GPcl) found on its surface to bind onto NPC1 to evade the vesicle. The researchers were able to clearly outline the crystal structure of the GPcl/NPC1 complex, thereby determining how it allows for the release of the virus from the vesicle. The crystal structure of any complex is the Holy Grail to understanding its function and significance in the cell. This information allowed the scientists to identify the exact location where NPC1 and GPcl bind to each other, which causes the membranes to fuse together, thus releasing Ebola from the vesicle.
Because Gao and colleagues were able to identify key structural information of Ebola and the host protein NPC1 they could determine how the two interact to allow the release of Ebola from a host vesicle. This information provides a map for which antibodies or small inhibitors could be designed to target this host/Ebola protein complex and prevent the infection.