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09.13.2016

Advanced imaging shows how deadly viruses evade defenses

Coronavirus that causes serious respiratory infections uses sugars to hide from antibodies

By Michael McCarthy  |  HSNewsBeat  |  Updated 1:30 PM, 09.13.2016

Posted in: Research

  • Alexandra Walls peers into a transmission electron microscope as part of her molecular structure studies. Michael McCarthy

A virus that causes severe respiratory infections evades our immune system by concealing proteins on its surface behind sugar “shields,” UW Medicine researchers report in a new study appearing in the journal Nature Structural & Molecular Biology.

The virus, called human coronavirus NL63, is a major cause of pneumonia in newborns. Italso can cause respiratory tract infections in other individuals, especially young children, the elderly, and those with weakened immune systems.

“Currently, there are no effective vaccines or therapies for human coronavirus infections,” said David Veesler,  

coronavirus structure
Veesler Lab
Three-dimensional structure of a coronavirus spike protein trimer (purple) wtih glycans (light grey) that help the virus evade the immune system
3D coronavirus spike protein trimer

assistant professor of biochemistry, who led the research. “These findings should help scientists develop vaccines and drugs targeting this virus and related coronaviruses.”

Coronaviruses make up a family of animal viruses that recently have been shown to jump from animals to humans. They have the potential to cause deadly worldwide pandemics. A coronavirus was responsible for the deadly severe acute respiratory syndrome (SARS) outbreak in 2003, in which one in ten people who became infected died. Another coronavirus is responsible for the ongoing outbreak of Middle East respiratory syndrome (MERS) which has a a fatality rate of 40 percent.

The new study’s  lead author is Alexandra C. Walls, a graduate student working with colleagues in the Veesler lab and DiMaio lab as well as with collaborators at the Institute Pasteur in Paris, France, and Utretch University in Utrecht, the Netherlands.  Her team used a technique called cryo-electron microscopy to examine spike proteins that are found over the surface of the virus. The look of these spike proteins  gives coronaviruses — which means “crown viruses” — their name.

The coronavirus spikes have two main purposes. First, they grab onto proteins found on the surface of  human and animal cells to allow the virus to invade. Once inside the cells, they participate in a process called fusion that releases the viral proteins and its RNA instructions.  This enables the the virus to take over the cell and begin copying itself.

Coronavirus spike proteins are of particular interest to medical researchers. They are virtually the only coronavirus surface protein  that can be easily targeted by antibodies, the immune proteins that bind to and help destroy invading viruses and bacteria.

To visualize the coronavirus spikes, UW Medicine researchers froze the proteins to the temperature of -180 degrees C. This technique fixes the proteins so they can be studied in a near-native state with a transmission electron microscope. Through this technique, the researchers achieved a protein model at a resolution of 3.4 ångström.

This resolution made it possible to establish the precise position of the individual amino acids that make up the spike proteins. Another technique used,  called mass spectrometry, t revealed the chemical composition of the different sugar components of the spikes. 

Walls and Veesler coronavirus study
Michael McCarthy
Alexander Walls and David Veesler review the formation of a virus molecular structure on a computer
Alexander Walls and David Veesler virus molecule

Using both techniques they were able to create a model that revealed the protein’s structure as well as the location of sugars, called glycans, that extend from the spike protein. The location of the glycans is important to know because our antibodies preferentially target and bind to proteins, not sugars. As a result, viral glycans, if properly placed, can shield proteins from host antibody attack.

The researchers found that the virus appears to tap into two strategies to elude the  attacking antibodies. First, the spike proteins are covered with more than 100 glycan moieties. These protect, among other areas, the part of spike that binds to the target cell. This hides this crucial structure from neutralizing antibodies.  Second, the protein flexes so that this binding area is tucked out of sight until it comes into contact with the target cell. With contact, the protein changes shape to expose the binding area so the virus can attach and enter the host cell. This occurs so quickly that there is little time for antibodies to detect the exposed binding area and trigger an immune attack.

Now, with much more precise understanding of the structure of the spikes, the existence of a glycan shield, and how the proteins flex, it may be possible to create vaccines and drugs that can effectively prevent or combat coronavirus infections, Veesler said.

The Sept. 12 Nature Structural & Molecular Biology article is, “Glycan shield and epitope masking of a coronavirus spike protein observed by cryo-electron microscopy.”  Read the paper.

The work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award numbers 1R01GM120553-01 and T32GM008268. Support also came from the Netherlands Organization for Scientific Research (NWO Rubicon 019.2015.2.310.006) and the European Molecular Biology Organisation (EMBO ALTF 933-2015) and the Institute Pasteur and the Le Centre National de la Recherche Scientifique. 

Tagged with: infectious disease, virus, respiratory infections
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