STOPPING A GLOBAL KILLER
Hoping to put an end to deadly outbreaks in Africa, Christopher Basler is on a mission to understand how Ebola and related viruses cause disease.
More than 40 years ago, Ebola virus was discovered near the Ebola River in what is now the Democratic Republic of Congo, formerly Zaire.
Ebola resembles the related Marburg virus, which was identified nine years earlier when infected nonhuman primates were imported to Europe from Africa, leading to an outbreak of severe disease.
Since then, these viruses have caused repeated outbreaks in several African countries, killing thousands and stoking fear around the world.
An outbreak of Ebola that began in the summer of 2018 has ravaged the Democratic Republic of Congo, claiming more than 2,000 lives with no end in sight. Just a few years earlier, from 2013 to 2016, West Africa experienced the largest Ebola outbreak since the virus was discovered, resulting in more than 28,000 cases and 11,000 deaths in Guinea, Liberia and Sierra Leone. The outbreak spread outside of the continent, reaching Europe and the United States, and caused an additional 36 cases and 15 deaths, according to the Centers for Disease Control and Prevention.
While scientists have made some breakthroughs in fighting the viruses, the work remains an uphill battle. Christopher Basler, director of the Center for Microbial Pathogenesis and a professor in the Institute for Biomedical Sciences, has dedicated much of his career to studying Ebola and Marburg, trying to understand how the viruses cause disease with hopes that his research will one day be used to create effective treatments.
Scientists believe Ebola and Marburg viruses were transmitted to humans from animals, most likely bats or nonhuman primates such as apes and monkeys. People are infected through direct contact with a sick animal’s blood, bodily fluids or tissue. Humans can also acquire the viruses from each other through contact with bodily fluids or objects contaminated with these fluids by an infected person.
Symptoms can appear from two to 21 days after contact with the virus, progressing from fever, aches, pains and fatigue to diarrhea, vomiting, abdominal pain and hemorrhaging, bleeding or bruising as the person becomes sicker.
The latest Ebola virus outbreak in the Democratic Republic of Congo has occurred in a war zone, making it even more difficult to fight the disease. In addition to the threat of violence faced by foreign medical personnel and public health officials, the local people are suspicious of outsiders and aren’t receptive to their assistance, hampering attempts to control the virus’ spread.
Basler began studying Ebola virus when he was a postdoctoral researcher at the Icahn School of Medicine at Mount Sinai and has remained committed to studying it because of the high stakes involved.
“Ebola virus is part of the filovirus family, which also includes several other viruses that can cause very severe, often fatal disease in humans,” Basler said. “That’s one motivation to study it.
“I think there’s the biodefense component as well,” he added. “These have been viewed for a long time as infectious agents that bioterrorists could use to cause havoc. We’d like to understand how it interacts with the host that it’s infecting and why that causes severe disease. Hopefully we can use that information to try to develop therapies to either block the virus or at least reduce the impact of the disease.”
When Basler was at Mount Sinai, he and his colleagues were studying influenza viruses and how they block the innate immune system, which defends against foreign substances in the body, to cause disease. In particular, the researchers were interested in an early, fundamental response called interferon response that enables cells to defend against viral infection. A study showed that influenza virus makes a protein that blocks this response.
The researchers proposed that Ebola virus also caused disease by blocking innate immune responses, such as interferon response, and set out to find a specific Ebola protein with this capability. Their early experiments showed that Ebola virus makes a protein called VP35 that can block interferon response.
In his recent work, Basler has found that expressing VP35 in hosts makes the cells unable to produce interferon, preventing the body from stopping Ebola infection. He has also figured out how to alter VP35 so that it’s ineffective.
“We’ve worked with collaborators to actually make recombinant Ebola viruses that have the mutated VP35, so you have an Ebola virus which now is no longer able to block interferon response,” Basler said. “We’ve shown that you can put that mutant virus into animals and now the virus is unable to cause disease. If you had a therapy that somehow prevented the function of VP35, then you presumably would have something of some therapeutic benefit.”
Basler and his team are now exploring the interactions between Ebola virus and host cell proteins that enable the virus to replicate, cause disease and spread efficiently. Ebola makes eight proteins.
“We found about 190 host proteins that interact with the virus proteins, and we’re trying to understand which of these interactions most contribute to disease,” Basler said. “The most interesting thing we found from the initial study was there are proteins in human cells that actually can suppress Ebola virus infection. In the end, the virus still causes terrible disease in people, but it is striking that there are proteins that slow the rate at which the virus grows.”
With much still to understand about Ebola, Basler hopes to soon have a lab at Georgia State that will allow him to work with the live virus.
Meanwhile, eradicating Ebola remains a distant goal. While scientists have created an effective vaccine against it, vaccines for Marburg and other related pathogens are still needed. Similarly, antibody-based therapies seem to be working against Ebola virus, but they have to be injected — requiring trained healthcare professionals — and they may not have a broad effect on the filovirus family, of which new members are still being identified.
“For Ebola virus, I think that you’d still like for there to be a small-molecule drug that you take orally to treat the infection,” Basler said. “It’s easier to administer and probably easier to deploy.”