Deadly disease pandemics are one of the most feared occurrences for public and global health researchers. They dread the day that such a disease manages to grip hold of a major population and then proceeds to spread internationally overnight. In all likelihood, such a disease will either be new or will be a known disease that mutates to become more virulent and lethal, catching everyone by surprise. There is, of course, the possibility for a member of the virus family with the highest kill count to reach pandemic levels, though it would require an extraordinary set of circumstances.
That doesn’t stop the public and scientists from worrying, however, and that fear can be easily seen in the reaction whenever a new outbreak of the Ebola virus occurs. The family that Ebola resides in, Filoviridae, is known for its viral hemorrhagic fevers, with every member of the brood being known to cause horrific illnesses.
Ebola’s Just As Evil Twin
Today we’ll be looking at the sibling disease to Ebola that is very biologically similar and that can have up to a 90% fatality rate, the Marburg virus. The biggest outbreaks of it happened in the early 2000’s, with a 2004 outbreak in Angola being the most severe and infecting several hundred people. Nearly all of those that caught the disease ended up dying.
Due to the method of how such viral infections propagate inside a host, by connecting their receptor binding sites with a receptor on a host cell and then injecting their genetic material, antibody therapies have been the main course of study to deal with them. If an antibody can be found or created that can match the binding site of a particular virus, then it should be able to significantly reduce the infectivity and virulence of the contagion, along with alarming nearby hunter killer cells and others to come deal with the invasion.
There have been no known antibodies, however, able to interact with Filoviruses, making treatment options limited. The believed main reason for this is due to the structure of the family, where they are made up of virions, viral particles, enveloped in a protein shell with only a single glycoprotein actually being expressed on the surface. The overall structure involves two glycoproteins, one to contain the receptor point and the other to house the machinery for fusing the virus to the cell wall, allowing access. The receptor point is only exposed after cleavage of these two proteins.
Marburg virus is known to use the same NPC1 receptor point as the Ebola virus, along with there being extra looped extensions special to this family of viruses that have been dubbed “wings”. These protruding loops form a hydrophobic pocket location after cleavage of the viral shell. Until now, the actual shape of these segments has not been investigated beyond research into Ebola itself.
Researchers at The Scripps Research Institute (TSRI) decided to change that after a previous study that looked at the blood of someone who had been infected with Marburg and survived was able to isolate resistant antibodies from the patient. That was in 2015. Then, last year in 2017, another study was able to determine that the antibody MR191 was the most potent out of the available options, giving superior protection against Marburg virus.
Therefore, the TSRI scientists chose to look more into this antibody and figure out exactly how it works and whether this might be applicable to other Filoviruses. An x-ray crystallography scan produced a high resolution map of the antibody and of Marburg, along with their interaction point.
The first thing they noticed is that Marburg’s extra loops are different than what was found in Ebola. In this virus, they fold around the exterior of the glycoprotein core to make the structure stable, a feat that is normally just covered by the other glycoprotein in the Ebola virus. This specific form gives the Marburg virus a unique structure that appears to be susceptible to antibodies formatted against it, hence the success of antibody MR191.
Additionally, the area of the glycoprotein with the receptor site seems to be flexible in movement in Marburg, unlike Ebola, allowing the antibody to get around the protective cap that’s meant to shield the virus from this sort of interference. This allows the antibody to block the receptor site and effectively compete for binding with Marburg as compared to the normal receptor site the virus tries to bind with.
When testing for escape mutants of the virus that were able to evade the antibody, it was found that their mutations were peculiar. They didn’t appear to change anything connected to the receptor site or protective cap, indicating that these structures, including the “wings”, may serve additional functions that need to be conserved, preventing mutations to these areas that would otherwise make the virus less fit for infection.
What did change in the escape mutants were far off structural sites in the viral glycoproteins, suggesting that either there is some sort of biochemical interaction between these sites and the receptor area or an as yet unknown mechanism that allows these far off structure changes to prevent the antibody from interfering with the receptor site.
One Down, Much More To Go
Sadly, all of this indicates that Marburg is very different from Ebola, at least in regards to preventive measures, so these types of antibodies can’t interfere with the spread of an Ebola virus infection. Different antibody measures will need to be taken. Hopefully there are other unique structures that can be exploited within Ebola’s biology and chemistry, but for now, we’ve learned quite a bit more about Marburg, another deadly disease that causes concerns about pandemics.
We have the first immunotherapy option to deal with Marburg outbreaks and that’s an important first step. Hopefully we will soon have many more steps that are taken.
Photo CCs: Beautiful….But Deadly from Wikimedia Commons