Studies by Tsinghua research team revealed a new mechanism of human antibodies against the Middle East respiratory syndrome coronavirus

2018-07-16 13:06:17

On July 10th 2018, a collaborative team headed by Professor Xinquan Wang at the School of Life Sciences and Professor Linqi Zhang at the School of Medicine of Tsinghua University published their new findings in Cell Reports revealing a novel mechanism of human monoclonal antibody MERS-4 against the infection of the Middle East respiratory syndrome coronavirus (MERS-CoV). Such a unique mechanism provides valuable addition for the combined use of antibodies against MERS-CoV infection.

Among the previously reported antibodies, the major mechanism of action involves competition with the cellular receptor DPP4 for binding to the receptor-binding domain (RBD) of the spike(S) glycoprotein. The newly reported MERS-4, however, recognized a unique epitope with unusual neutralization mechanism in that it approached the RBD from the outside of the RBD-DPP4 binding interface. Such binding resulted in the folding of the β5-β6 loop towards a shallow groove on the RBD interface critical for accommodating DPP4 thereby indirectly disrupts interaction between the receptor binding domain and the receptor DPP4. Structural modeling also revealed that MERS-4 preferentially binds to the RBD only in the “up” position in the S trimer. Lastly, MERS-4 demonstrated synergy with several reported antibodies. These results indicate that MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4.

Since the emergence of the MERS-CoV in Saudi Arabia in 2012, the MERS-CoV epidemic has persisted throughout the Arabian Peninsula and spread to other countries such as South Korea in 2015. The infected cases are largely due to contact with dromedary camels, which are believed to be a major reservoir host for MERS-CoV and the immediate source of human infection. Compared to SARS-CoV with a fatality rate of approximately 10%, MERS-CoV appears to be more deadly with fatality rate as high as 35%. All these facts indicate that MERS-CoV will remain as a severe and long-time threat to global health and highlight the urgent need for effective prophylactic and therapeutic measures.

Teams headed by Professor Xinquan Wang and Professor Linqi Zhang have been closely working together since the emergence of the MERS-CoV in Saudi Arabia in 2012. They have made significant contribution to better understand the structural and functional interaction between MERS-CoV Spike protein and receptor DPP4. They are also among the first in the world to isolate and characterize human antibodies to disrupt Spike protein and DPP4 interaction thereby inhibit MERS-CoV infection. In the newly published studies, Prof. Xinquan Wang (School of Life Sciences) and Prof. Linqi Zhang (School of Medicine) shared the co-corresponding authors. Senyan Zhang (PhD student from the School of Life Sciences), Panpan Zhou (PhD student from the School of Medicine), and Pengfei Wang (PhD student from the School of Life Sciences) are the co-first authors. This research was funded by the National Key Technologies R&D Program, the National Natural Science Foundation of China, and partially by the Bill & Melinda Gates Foundation. Professor Xinquan Wang and his group was also supported by the Beijing Advanced Innovation Center for Structural Biology.

Crystal structure of MERS-4 and RBD complex

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