Though the latest outbreak of Ebola appears to be nearing an end, the virus may pose a threat again in the future. Thus a drug to help individuals survive this dangerous infection, which has mortality rates up to 90 percent, is in intense demand.
A new avenue of research, led by scientists at Penn’s School of Veterinary Medicine, holds promise to help fight infections—not just of Ebola, but of other dangerous pathogens, including Marburg, Lassa, and Junin viruses.
“Our work is aimed at handicapping the virus enough for the immune system to be able to respond,” says Bruce Freedman, an associate professor in Penn Vet’s Department of Pathobiology, who coauthored the work with Penn Vet’s Ronald Harty, a professor of microbiology and pathobiology.
Their study, published last month in PLOS Pathogens, aimed to quash the virus by blocking a key host cell function upon which the pathogen relies. In this case, Freedman, Harty, and colleagues focused on calcium signaling, a key regulator of many cell processes, which earlier studies suggested is involved in virus production.
In the initial stages of the research, the Penn Vet team used non-infectious viral-like particles, or VLPs, which behave like the virus in terms of how they exit from a cell, a process known as budding. They found that while VLPs seemed to trigger host cells to elevate their levels of internal calcium, mutating a calcium channel protein, ORAI1, in those cells reduced the calcium uptick. So did a drug that blocks the ORAI1 channel.
The researchers also found that production of Ebola, Marburg, Lassa, and Junin virus VLPs were all significantly diminished by up to 100-fold in the Orai1 mutant cells, an indication that budding of these hemorrhagic fever viruses relies on the ORAI1-dependent calcium signaling. The use of Orai1 inhibitors also blocked Ebola and Marburg VLP production.
Next the research team performed experiments with live viruses in the United States Army Medical Research Institute of Infectious Disease’s BSL-4 laboratory. Mutant ORAI1 cells infected with Ebola, Marburg, Junin, or Lassa viruses exhibited impaired virus budding compared with normal unmutated cells and an Orai1 inhibitor also produced a similar dose-dependent block in the ability of viruses to exit the cell, effectively limiting their ability to spread.
The team is working to refine the inhibitors to improve their effectiveness and reduce the likelihood of any side effects.
“It could be that this type of drug would be part of a cocktail therapy, like is used for HIV, to knock the virus down at different stages of its life cycle,” says Harty.