Monoclonal against Marburg: X-rays track antiviral effect

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  • Published: Jan 15, 2018
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Monoclonal against Marburg: X-rays track antiviral effect

Viral neutralization

TSRI Graduate Student Liam King and Professor Erica Ollmann Saphire, PhD, led the new study (Photo by Madeline McCurry-Schmidt)

X-ray studies have revealed how a human monoclonal antibody known as MR191, neutralizes the Marburg virus by mimicking the host receptor and plugging into a spot on the viral surface through a receptor binding site.

Marburg virus is a haemorrhagic fever virus related to Ebola and Cueva viruses. It is extremely dangerous with the WHO ranking it as a Risk Group 4 Pathogen requiring biosafety level 4-equivalent containment. It is transmitted by fruit bats to people and non-human primates but can also be transmitted in bodily fluids via sexual contact or through broken skin. It leads to cause bleeding (haemorrhaging), fever and other symptoms similar to those seen in Ebola. There is no treatment and the mortality rate is almost 9 out of 10 people infected (88 percent). An outbreak in Angola in 2005 ripped through the community killing 329 of 374 infected patients.

There is some hope of a way to treat the disease, however, with news from The Scripps Research Institute (TSRI) of insights into how a monoclonal antibody interacts with the Marburg virus. The work builds on earlier scientific studies into a human antibody known as MR191 which was known to neutralize Marburg. The new research reveals, through X-ray studies, exactly how the mAb targets the virus.

Marburg information

In the new work, Erica Ollmann Saphire and her colleagues at TSRI and at the Vanderbilt University Medical Center, Nashville, Tennessee, the University of Texas Medical Branch, Galveston, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, and the California Institute of Technology, Pasadena, California, have mapped the structure of the virus. Their high-resolution X-ray crystal structure of MR191 targeting and neutralizing the virus is detailed in the journal Cell Host & Microbe. The new information could ultimately lead to a vaccine-type strategy that triggers antibody production in patients.

"This is the first antibody therapeutic found that could treat Marburg,” says Ollmann Saphire. Graduate student Liam King adds that, "With this new structure, we can start to see how this treatment works. We have also learned new things about the virus itself that could lead to new treatments and vaccines."

On a wing

The crystallographic structure shows that MR191 mimics the host receptor on the virus and so latches on to the viral surface through the receptor binding site. This very effectively blocks the virus from attaching itself to a host cell and so halts infection. The X-ray structure also reveals something of the architecture of the virus, showing what the team describes as a wing that protrudes from its side. This wing appears to be one of only two sites on the virus to which human antibodies can bind. The behaviour of this "wing" represents a significant difference between Marburg and its close viral relative Ebola. Unlike the wing on Ebola virus, the Marburg wing folds around the outside of the glycoprotein spike.

"That finding and others in this structure tell us that Marburg is constructed differently from its cousin, the Ebola virus," explain Ollmann Saphire. "That means the therapeutic strategy for one may need to be different from the other."

In addition to differences in wing folding, the team also points out that while both viruses use a structure called a glycan cap to shield the vulnerable receptor binding site from the human immune system, the X-ray work reveals that MR191 can circumvent the glycan cap on Marburg virus, a phenomenon that has not been observed in efforts to defeat Ebola virus. The next step will be to investigate how known mutations in Marburg allow those strains to evade such antibodies nevertheless. Insights from that ongoing work will allow scientists to devise second-line treatments.

The Vanderbilt University collaborators have now licensed MR191 to a commercial partner and the group hopes to see it enter clinical trials soon.

Related Links

Cell Host Microbe 2018, 23, 101-109: "The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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