Defanging a Killer Virus
SARS-CoV-2, the virus that causes COVID-19, may have caused the first global pandemic in more than a century, but it’s not the only pathogen with the potential to wreak havoc. Since it was discovered more than 40 years ago in what is now the Democratic Republic of Congo, Ebola and the related Marburg virus, which was identified nine years earlier, 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 ravaged the Democratic Republic of Congo, claiming more than 2,000 lives. Just a few years earlier, from 2013 to 2016, Ebola infected 28,000 people and caused 11,000 deaths in Guinea, Liberia and Sierra Leone. That outbreak spread outside the continent, too, reaching Europe and the United States. This year, even as the world is reeling from the COVID-19 pandemic, Ebola has reemerged in both Democratic Republic of Congo and Guinea in West Africa, and the Marburg virus has caused an outbreak in West Africa.
Scientists believe Ebola and Marburg viruses, like SARS-CoV-2, are zoonotic, meaning they jumped to humans from animals, most likely bats or nonhuman primates such as apes and monkeys. Unlike SARS-CoV-2, which spreads through respiratory droplets, Ebola is transmitted through direct contact with a sick animal’s blood, bodily fluids or tissue or through contact with bodily fluids from an infected person. Symptoms can appear from two to 21 days after contact with the virus, progressing as the person becomes sicker. On average, Ebola kills about half of those who become infected with the virus.
While scientists have made some breakthroughs in fighting these viruses, the work remains an uphill battle because outbreaks are unpredictable and drugs to treat these infections are limited. 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, working to better understand how these viruses interact with a host and why they result in such severe disease. The work is high stakes. While not as transmissible as COVID-19, Ebola virus has demonstrated its capacity to cause large epidemics and modern travel allows for the possibility of infections spreading to just about any place people live.
In addition, because Ebola and other members of the filovirus family can cause severe, often fatal disease in humans, “there has long been concern that these viruses could be used by bioterrorists as infectious weapons,” he says.
Basler began studying Ebola virus 20 years ago, when he was a postdoctoral researcher at the Icahn School of Medicine at Mount Sinai. He and his colleagues were researching influenza viruses and how they block the innate immune system — which defends the body against foreign substances — to cause disease. In particular, the researchers were interested in an early, fundamental immune response called the interferon response, which enables cells to defend against viral invaders. (Interferons are proteins produced by cells in response to infection). Their research showed that the flu virus makes a protein that blocks this response.
The team proposed that Ebola virus also caused disease by blocking innate immune responses, such as the interferon response, and began searching for a specific Ebola protein with this capability. Their early experiments showed that Ebola virus makes a protein called VP35 that can block the interferon response.
In his recent work, Basler has found that expressing VP35 in hosts makes their cells unable to make interferon, preventing the body from stopping Ebola infection. As a countermeasure, he and his collaborators have genetically altered Ebola viruses to produce a mutated version of VP35 that is unable to block interferon production.
“We’ve shown that you can put that mutant virus into animals and now the virus is unable to cause disease,” says Basler, who is also a Georgia Research Alliance Eminent Scholar. “If you had a therapy that somehow prevented the function of VP35, then it should slow the virus and reduce disease.”
Basler and his team are now exploring the interactions between Ebola virus and host cell proteins that enable the virus to replicate, causing disease and spreading efficiently. In a study released in August, they reported the surprising discovery that human cells contain proteins that can slow Ebola virus growth. Understanding how this inhibition occurs could suggest novel ways to treat infections.
“We found about 190 host proteins that interact with the virus’s eight proteins, and we’re trying to understand which of these interactions contribute most to disease,” Basler said. “The most interesting thing we found from the initial study is 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.”
While scientists have made some progress against Ebola and related viruses, there’s still lots of work to be done. An Ebola vaccine has been developed, but vaccines for Marburg and other similar pathogens are still needed. Injectable antibody-based therapies seem effective against Ebola, but they have to be administered by trained healthcare professionals — and they may not have a broad effect on the rest of the filovirus family.
“To quickly and effectively quash Ebola outbreaks, I think there needs to be a small-molecule drug that you take orally to treat the infection,” Basler says. “Hopefully, our research can be used to develop therapies that block the virus or at least reduce the impact of the disease.”
Portrait by Steven Thackston