In a new study, Researchers from institutions such as the University of Washington studied human monoclonal antibodies isolated from survivors of severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) caused by coronavirus, which revealed surprising immune defense strategies against deadly viruses. Atomic and molecular information about these highly potent antibodies may provide new insights into preventing these serious and sometimes fatal pulmonary infections. The results were published online on Cell on January 31, 2019 under the title “Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion”.
Currently, there are no vaccines or specific treatments for six coronaviruses that can infect humans. Some of these coronaviruses cause only common cold-like symptoms, but others cause fatal pneumonia. Past deadly outbreaks in several countries have heralded the possibility of a coronavirus-mediated pandemic. In addition, genetic surveillance of coronavirus in bats and the natural prevalence of MERS coronavirus (MERS-CoV) in unimodal camels suggest that previous outbreaks may not be uncommon. Animal/human species barriers may be crossed again and lead to the emergence of new coronavirus in the future. As part of the anticipation and preparation plan, infectious disease scientists around the world are working to develop an anti-coronavirus library. Veesler and his team are trying to understand how SARS coronavirus (SARS-CoV) and MERS-CoV infect humans and how their presence triggers an immune system response. They are particularly interested in how neutralizing antibodies target coronavirus cell invasion complexes.
Coronavirus has multifunctional surface spikes, which are composed of spiny glycoprotein that recognize and bind receptors located on the surface of host cells. They then fuse the virus with the cell membrane. Coronavirus uses trimer prickle glycoprotein as their molecular invasion tool. These spiny glycoproteins are densely decorated on the surface of coronavirus. Spike glycoprotein is the key to the infectivity and pathogenicity of coronavirus. They are the targets of neutralizing antibodies and the focus of subunit vaccine design.
Veesler’s team has previously studied the structural state of coronavirus spikes before and after the membrane fusion reaction. They observed a large number of conformational changes in the spiny glycoprotein. However, the details of the activation of this membrane fusion cascade reaction are still unclear. In this new study, by using cryogenic electron microscopy and other powerful techniques, the researchers provide new insights into how neutralizing monoclonal antibodies from SARS and MERS survivors can inhibit 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.
The researchers found that neutralizing monoclonal antibodies from 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 effect: they functionally mimic receptor binding and induces conformational changes in viral spikes, leading to membrane fusion. This trigger appears to be driven by a molecular ratcheting mechanism. “This discovery is an unprecedented example of functional simulation: antibodies activate membrane fusion by reproducing the role of receptors,” the researchers said.” The study used molecular imaging to describe the structure of SARS and MERS coronavirus spike glycoprotein in complexes with their respective monoclonal antibodies.
The researchers also provided a carbohydrate blueprint for modifying these spiny glycoproteins throughout the virus environment. Coronaviruses use this strategy to mask vulnerable parts of their fusion complexes, thereby limiting antibody exposure to this fragile part and exposing it only when host cells are recognized and infected.