In a new study, researchers from research institutions such as the University of Washington in the United States studied monoclonal antibodies which were isolated from survivors of the severe acute respiratory syndrome (SARS) or Middle East Respiratory Syndrome (MERS) caused by the coronavirus. These monoclonal antibodies reveal an alarming immune defense strategy against deadly viruses. Atomic and molecular information for these highly potent antibodies may provide new insights into these serious and sometimes fatal lung infections. The results of the study were published online in the Cell Journal, under the heading “Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion.”

 

Currently, there are no vaccines or specific therapies for six coronaviruses that can infect humans. Some of these coronaviruses cause only common cold-like symptoms, but other coronaviruses cause lethal pneumonia. The fatal outbreaks that have occurred in several countries in the past indicate that a coronavirus-mediated pandemic is likely to occur.

 

 

In addition, the genetic monitoring of coronavirus in bats and the fact that MERS coronavirus (MERS-CoV) is naturally prevalent in dromedary camels suggest that previous outbreaks may not be uncommon. Animal/human species barriers may be crossed again and lead to the emergence of new coronaviruses in the future.

 

As part of the anticipation and preparation program, infectious disease scientists around the world are working to develop a library of anti-coronaviruses. Veesler and his team are trying to understand how SARS-CoV and MERS-CoV infect humans and how their presence causes the immune system to respond. They are particularly interested in how neutralizing antibodies target the cellular invasion complex of coronavirus.

 

Coronaviruses have versatile surface spikes, which are recognized by spikes composed of spike glycoproteins and bind to receptors located on the surface of host cells. They then fuse the virus and cell membrane together. Coronaviruses use trimer spike proteins as their molecular invasion tool.

 

These spike glycoproteins are densely decorated on the surface of the coronavirus. Spike glycoproteins are key to the infectivity and pathogenicity of coronaviruses. They are targets for neutralizing antibodies and are the focus of subunit vaccine design.

 

The Veesler team has previously studied the structural state of coronavirus spikes before and after this membrane fusion reaction occurs. They observed a large number of conformational changes in the spike glycoprotein. However, details regarding the activation of this membrane fusion cascade reaction remain unclear.

 

In this new study, by using cryo-electron microscopy and other powerful techniques, these researchers provide new insights on how the neutralizing monoclonal antibodies from SARS and MERS survivors suppress the two coronaviruses (SARS-CoV and MERS-CoV) at the molecular level. Their findings also help to elucidate the unusual nature of coronavirus membrane fusion activation.

 

These researchers found that neutralizing monoclonal antibodies from both SARS and MERS survivors prevented the interaction between their respective viral spikes and receptors on the host cell membrane. Neutralizing monoclonal antibodies from SARS survivors also have some unexpected effects: they functionally mimic receptor binding and induce viral spikes to undergo conformational changes leading to membrane fusion. This trigger seems to be driven by a molecular ratcheting mechanism.

 

“The discovery is an unprecedented example of functional modeling: antibodies activate membrane fusion by reappearing receptors,” the researchers noted.

 

This study used molecular imaging to describe the structure of SARS and MERS coronavirus spike glycoproteins in complexes with their respective monoclonal antibodies.

 

The researchers also provided a carbohydrate blueprint for modifying these spike glycoproteins throughout the viral environment. Coronaviruses use this strategy to mask the fragile parts of their fusion complex, thereby limiting antibody exposure to this vulnerable part and exposing it only when identifying and infecting host cells.

 

 

Reference

Alexandra C. Walls et al. Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion. Cell, 2019, doi:10.1016/j.cell.2018.12.028.