Scientists at Emory University and the University of St. Andrews have solved the structure of a key protein from Lassa virus, which is endemic to West Africa and can cause a deadly hemorrhagic fever.
The structure reveals how the virus evades its host's immune system, and how it hijacks infected cells' vital machinery in a process scientists call "cap-stealing." Details of the structure could guide future efforts at antiviral drug discovery and vaccine development.
The results are published in this week's issue of Nature.
Lassa virus represents a family of viruses - arenaviruses -- whose natural hosts are rodents and cause hemorrhagic fevers in Africa and South America. New varieties of arenavirus continue to emerge, such as the deadly "Lujo" virus identified recently in Zambia and South Africa.
Lassa virus infects 100,000 to 300,000 people every year in West Africa, with an estimated 5,000 deaths, according to the Centers for Disease Control and Prevention. Most people infected have a mild illness, but about 20 percent have a severe multisystem disease with internal bleeding and immune suppression. Around one percent of all infections are fatal. A common complication of infection is deafness.
Lassa virus' NP (nucleoprotein) is the first protein produced after viral infection and the most abundant component of the virus. To study the properties of Lassa virus NP, virologists at Emory collaborated with structural biologists at University of St. Andrews, who examine the details of protein structure with X-rays. The X-ray data was collected at the Diamond Light Source, the United Kingdom's national synchotron facility. The Nature paper's co-senior authors are Changjiang Dong, PhD, a Wellcome Trust fellow at St. Andrews, and Yuying Liang, PhD, and Hinh Ly, PhD, both assistant professors of pathology and laboratory medicine at Emory University School of Medicine. The first author is St. Andrews postgraduate student Xiaoxuan Qi.
Human cells can usually detect viral infection with internal alarm systems that sense the presence of viral components, such as viral RNA or DNA. Arenaviruses such as Lassa virus have genomes made of RNA instead of DNA. Because cells send out molecules called interferons to muster the immune system against the virus, many viruses have developed ways to block interferon production.
Based on the X-ray structure, the authors discovered that Lassa virus NP has the ability to chew up RNA molecules. By testing versions of Lassa virus NP with that part of the protein disabled, they confirmed that this property is needed to suppress cells' interferon production.
"What I think is exciting is that we are seeing a new viral mechanism for suppressing the interferon response," Liang says. "This is the first viral protein anyone has found that destroys the RNA molecules that are the triggers for these internal alarms."
What remains a puzzle is how the virus avoids chewing up cellular and viral RNA indiscriminately, she says.