Host cell factors involved in Ebola virus entry and spread

The success of Ebola as a highly pathogenic RNA virus depends critically on its ability to interact with host cells. Ebola's relationship with the host involves a delicate balance between cellular factors that either promote or inhibit the virus replication cycle. Cellular cathepsins are among the factors required by Ebola during virus entry. Cathepsins B and L, which are proteases present in low-pH endosomes, process the Ebola glycoprotein (GP) from a 130-kDa form to an 18-kDa fragment. Here we show that the 18-kDa form of GP is responsible for enhanced virion binding and infectivity of target cells. These results suggest that cathepsin priming activates the receptor binding potential of Ebola GP. While cellular factors like cathepsins are beneficial for Ebola propagation in cells, other host cell components exist to limit the extent of Ebola virus replication and spread. Tetherin is a recently identified antiviral restriction factor that blocks the release of HIV-1 and other retroviruses from infected cells. Our results demonstrate that both human and mouse Tetherin are broad-spectrum antiviral factors that restrict not only HIV, but the spread of Ebola virus as well. However, Ebola appears to have evolved a mechanism to counteract the negative selective pressure exerted by Tetherin. We have found that expression of the Ebola GP in the absence of other viral genes potently antagonizes the activity of Tetherin and promotes Ebola virus release, displaying a similar effect as the HIV-1 accessory protein Vpu. In fact, Ebola GP can substitute for HIV-1 Vpu, promoting the release of HIV-1 from the cell surface and suggesting that GP and Vpu interact with a common cellular target. Additionally, Ebola GP physically associates with Tetherin suggesting a mechanism whereby GP interferes with the activity of this antiviral factor. Understanding how Ebola GP both relies on cathepsins and interacts with Tetherin may lead to the development of new therapeutics for Ebola infection and perhaps other viruses as well.