Studies of human monoclonal antibodies isolated from survivors of coronavirus-induced severe acute respiratory syndrome (SARS) or Middle-East respiratory syndrome (MERS) are unveiling surprising immune defense tactics against fatal viruses. Currently, no vaccines or specific treatments are available for any of the six coronaviruses that can infect humans. Some of these coronaviruses cause only common-cold like symptoms, but others provoke lethal pneumonias.
An international team headed by UW Medicine scientists is among those attempting to understand how SARS and MERS coronaviruses infect humans, and how their presence elicits a response from the immune system. The research group is particularly interested in how neutralizing antibodies target the coronavirus’ cell-invasion machinery.
Previous studies in the Veesler lab at UW Medicine looked at the structural states that occur in the coronavirus spike before and after the membrane fusion reaction. The researchers saw large conformational changes in the spike glycoprotein. Details about activation of the membrane fusion cascade, however, remained unclear.
Using cryo-electron microscopy and other powerful technologies, the researchers gained insight into how the neutralizing monoclonal antibodies from the SARS and MERS survivors inhibit the viruses at the molecular level. Their findings also helped elucidate the unusual nature of coronavirus membrane fusion activation.
The researchers found that both the SARS and the MERS coronavirus antibodies blocked the virus spikes from interacting with the receptors on the host cell membrane.
The SARS coronavirus antibody also did something unexpected: it functionally mimicked receptor-attachment and induced the spike to undergo conformational changes leading to membrane fusion. This trigger seems to be driven by a molecular ratcheting mechanism.
Alexandra C. Walls, Xiaoli Xiong, Young-Jun Park, M. Alejandra Tortorici, Joost Snijder, Joel Quispe, Elisabetta Cameroni, Robin Gopal, Mian Dai, Antonio Lanzavecchia, Maria Zambon, Félix A. Rey, Davide Corti, David Veesler. Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion. Cell, Jan. 31, 2019; DOI: 10.1016/j.cell.2018.12.028