Writing about their work in the 13 September issue of the online open access journal PLoS Pathogens, lead researcher Erica Ollmann Saphire, and colleagues, suggest their breakthrough offers new targets for drugs and vaccines.
MarburgMarburg is a genetically unique, animal-borne, RNA filovirus that causes a rare but severe type of hemorrhagic fever which affects both humans and non-human primates. Infections typically appear in sporadic outbreaks throughout Africa. An outbreak in Angola in 2005-06, which started in a pediatric ward, killed 88% of those infected.
The virus was discovered in the 1960s after lab scientists in Marburg in Germany and other labs in Europe, became infected. The lab in Marburg was using African green monkeys and their tissue to develop a polio vaccine. The five species of Ebola virus are the only other known members of the filovirus family.
The virus has been imported into the United States (Colorado) and the Netherlands by tourists who visited Africa.
There is currently no cure for Marburg infection, which is spread when people come into contact with bodily fluids from an infected person or animal. Most people die within two weeks, from dehydration, massive bleeding and shock: a small proportion have naturally strong and immediate immune responses and survive.
Hallmarks of Virus Infection""The immune system is designed to recognize certain hallmarks of virus infection," Ollmann Saphire says in a press statement.
"When these are sensed, an immediate antiviral defense is launched. However, the Marburg and Ebola viruses mask the evidence of their own infection. By doing so, the viruses are able to replicate rapidly and overwhelm the patient's ability to launch an effective defense," she explains.
The immune system relies on being able to recognize the double stranded RNA (dsRNA) at the heart of viruses: this "key signature" of virus infection is detected by "host sentry proteins" like RIG-I and MDA-5, write the authors.
Fingering the VP35 ProteinPrevious studies had already identified that the viral protein VP35, common to both Ebola and Marburg, was important to immunosuppression.
And they had also, from examining the crystal structure of the protein from two ebolaviruses, showed that it formed "an asymmetric dimer to cap the ends of dsRNA molecules".
But what was not clear, until this study, was whether the protein was able to mask the lengths of dsRNA that lie between the ends of the molecules.
VP35 Surrounds and Masks All the Viral dsRNAIn this new study, Ollmann Saphire and colleagues show that VP35 does mask the whole of dsRNA: they did further crystal analysis and were surprised to find the VP35 protein in Marburg envelops all the virus's double-stranded RNA, masking it from immune system detection.
"Rather than binding only the ends, the Marburg virus VP35s spiral around the dsRNA backbone, continuously coating it. Additional biochemical experiments indicate that this continuous coating occurs in solution, and that like the ebolaviruses, Marburg virus VP35 is also able to cap the dsRNA ends, even though this was not apparent in the crystal structure," they write.
"Together, this work illustrates how Marburg virus VP35 prevents recognition of dsRNA by backbone-sensing immune sentry molecules and provides an additional avenue for antiviral development," they conclude.
Grants from the Burroughs Wellcome Fund and The Skaggs Institute for Chemical Biology at Scripps Research helped fund the study.
Written by Catharine Paddock PhD