Research Front: Mechanisms of Ebola Virus Infection
There’s nothing quite like a deadly disease to excite the science writer. The finding, just weeks ago as I write this, that the Ebola virus apparently displayed airborne transmission from pigs to non-human primates—meaning it did not require close contact with the bodily fluids of an infected host to jump to a fresh host—is pretty scary. And the counter, at about the same time, that the rise in hemorrhagic diseases such as Ebola, Marburg and Lassa reflects emerging diagnoses rather than emerging diseases, is scant comfort. So how are things going in the search to understand pathogens like Ebola virus?
A current area of research concentration on Ebola virus recently tripped the sensors of the Thomson Reuters Research Front database. These Research Fronts represent discrete areas of related research, identified entirely through automated analysis of citation patterns in the published literature—specifically, analysis of papers that are frequently cited together, or “co-cited.” Each front consists of a “core” of co-cited foundational papers along with the subsequent reports that have cited the core.
The accompanying table presents the eight core papers in a current Front involving the molecular mechanism of infection by Ebola and related pathogens. Although eight reports constitute a comparatively small core, these are notable in all being published within the last two years; a Front with recent core literature generally indicates an emerging area of research undergoing rapid change.
Anchoring this Front on Ebola virus is a medical review of the disease in The Lancet, but cited at #2 and #3 are two strangely complementary papers published back to back in Nature.
While the thought of imminent therapies may calm some fears, Ebola and other hemorrhagic viruses continue to pose a threat to people and to our closest relatives.
The #2 paper boasts no fewer than four senior scientists: John Dye at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Sean Whelan at Harvard Medical School, Kartik Chandran at Albert Einstein College of Medicine, and Thijn Brummelkamp, then at the Whitehead Institute for Biomedical Research.
The team modified a line of cells from a patient with chronic myeloid leukemia. These cells, known as KBM7 cells, are almost entirely haploid. They contain only one of each pair of chromosomes, except for chromosome 8, which is diploid. While trying to turn KBM7 cells into pluripotent stem cells, the researchers created a cell line—called HAP1—that was haploid for all chromosomes. This makes it much easier for researchers to examine the effect of knocking out a particular gene, because there is only one copy to destroy. The team created a pool of HAP1 cells mutated more or less at random to knock out individual genes, and then exposed those cells to a virus designed to use Ebola’s method of entering the cell. Cells resistant to infection by this Ebola-like probe were then sequenced, picking up 67 different mutations that disrupted all subunits of a complex called the homotypic fusion and vacuole protein-sorting (HOPS) complex. A further 39 mutations disrupted a cholesterol transporter protein called Niemann-Pick C1 (NPC1).
Mutations to NPC1 cause one form of Niemann-Pick disease, a fatal metabolic disorder. But skin cells from patients with Niemann-Pick disease are resistant to infection by Ebola virus and its close cousin Marburg virus, even though those cells remain susceptible to a host of other kinds of virus. And cells in which NPC1 has been deliberately altered are also resistant.
PICKING A TARGET
Which leads directly to the #3 paper in this Research Front, and a team led by James Cunningham, of Harvard Medical School and Brigham and Women’s Hospital. Starting in 2006, long before any clues about NPC1 had emerged, this group surveyed a vast library of about 40,000 different small chemical compounds, looking for anything that would block infection by Ebola virus. One chemical inhibited the growth of the test virus by more than 99%. More than 50 chemical analogues of this compound revealed one that was even more effective. And the target of these inhibitory compounds was NPC1 itself, which makes NPC1 a good target for an Ebola therapy.
Kartik Chandran, the only author common to both papers, is pursuing the idea of blocking Ebola’s entry to host cells as an antiviral therapy. But if a defective NPC1 gene results in a fatal disease, won’t efforts to disrupt NPC1 be harmful?
“We think (and hope!) that we should be able to safely inactivate NPC1 for short periods of time (weeks at most) to treat Ebola-infected patients, since this is an acute viral infection,” Chandran told ScienceWatch.
The accumulation of cholesterol within cells that is the signature of Niemann-Pick disease takes much longer to be dangerous. Recent studies of the details of Ebola’s infective mechanism make up most of the rest of the core papers in this Research Front. But while the thought of imminent therapies may calm some fears, Ebola and other hemorrhagic viruses continue to pose a threat to people and to our closest relatives.
Ebola and other viruses are known to kill wild gorillas and chimpanzees. Sadie J. Ryan, of SUNY Syracuse, and Peter Walsh of the University of Cambridge, modeled the impact of these diseases on endangered populations of these species. Using demographics derived from the well-studied gorillas of the Virunga Mountains in Rwanda, they estimate that it could take 131 years for the population to recover from a single outbreak of Ebola. And, they write, “[e]ven this bleak picture of resilience for a well-known gorilla population is highly optimistic." What is to be done? Ryan and Walsh examine various options, and recommend treatment and vaccination. Both will require considerably more research, especially for the more deadly diseases like Ebola, but the recent emergence of the Ebola Research Front suggests that progress is picking up.
Dr. Jeremy Cherfas is Senior Science Writer at Bioversity International, Rome, Italy.
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