|Ebolavirus under an electron microscope--Courtesy of CDC|
As the world learned all too well recently, Ebola virus can kill its host in a matter of days, harnessing the infected cells' protein machinery to generate more virus particles and rapidly spreading to other cells. The time it takes for the host's immune system to recognize the invaders and clear them is important for an effective response. Now, researchers claim to have a novel solution that buys the host more time to clear the virus.
Research conducted at the University of Pennsylvania School of Veterinary Medicine, demonstrated that by blocking a calcium signalling pathway they could reduce the ability of the virus to exit a host cell and spread. And this was effective in Ebola virus, as well as the similarly potent Marburg, Lassa and Junin viruses.
"Our work is aimed at handicapping the virus so that the immune system has time to respond." said Bruce Freedman, who joins Ronald Harty of the same department to share authorship for the new study, published in the journal PLOS Pathogens.
Their work initially showed a calcium channel called ORAI1 to be crucial to the survival and infectivity of viral-like particles (VLPs)--which behave like viruses but are safer and more convenient to use in the lab. When they mutated ORAI1 in a cultured cell line they found that VLPs were significantly lower compared to cells without the mutation.
They then went on to show STIM1, a potential regulator upstream of ORAI1, also positively regulated VLP budding and survival. They tried three ORAI1 inhibitors in normal cells infected with VLPs and observed a reduction in VLPs using all inhibitors.
Taking this forward into live Ebola, Marburg, Junin or Lassa viruses, they observed a similar result and showed that the ORAI1 inhibitors could lower VLP budding in a dose-dependent way. From this finding, Freedman and the team were confident interrupting the calcium signalling required by the virus, leads to the virus becoming arrested at the host cell, preventing its exit from the cell.
"We saw this in each of the viruses, so there seems to be a common requirement for calcium in the late stages of viral budding from the cell," Freedman said.
"One of the exciting aspects of this approach," Hardy said, "is its ability to provide broad-spectrum inhibition of budding of hemorrhagic fever viruses that we're interested in, as well as other viruses that bud using similar mechanisms."
- here's the release