Cryo-EM structures of Měnglà virus GP reveal combined Ebola- and Marburg-like epitope masking strategies for antibody evasion.
Longyu Wang1,2,3
Binqian Zou3,4
Banghui Liu3
Yong Ma3
Lu Xue3
Gul Habib3
Xinglou Yang5
Xinwen Chen2
Jiantao Chen4
Jincun Zhao2,4,6
Ying Zhang7
Zifeng Yang2,4
Jun He1,3
Xiaoli Xiong1,2,3
Affiliations7 institutions
Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangdong Provincial Key Laboratory of Protein Modification and Disease, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China.
State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.
Key Laboratory of Genetic Evolution and Animal Models, Yunnan International Joint Laboratory of Zoonotic Viruses, Yunnan Key Laboratory of Biodiversity Information, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China.
PMID 422475612026Proc Natl Acad Sci U S Aengppublish
Ebola virus (EBOV) and Marburg virus (MARV) are highly lethal filoviruses that cause severe hemorrhagic fever in humans. A recently identified bat-borne filovirus, Měnglà virus (MLAV), uses the same NPC1 receptor as EBOV and MARV, raising concerns about its potential cross-species transmission. Here, we report cryo-EM structures of the MLAV surface glycoprotein (GP) in its unbound form and in complex with the MARV-neutralizing antibody MR191. MLAV GP exhibits distinctive structural features in the Wing and heptad repeat 1D (HR1D) regions, retains a visible Cap structure even after protease treatment, and contains a MARV GP-like α2 helix. MR191, a broadly neutralizing marburgvirus antibody that targets the conserved NPC1 receptor-binding pocket in MLAV GP, nonetheless exhibits impaired neutralizing activity, likely due to shielding by the MLAV Cap. In addition, the MLAV mucin-like domain, α2 helix, and HR1A region hinder binding by representative broadly neutralizing ebolavirus antibodies targeting the GP-waist, including 6D6, CA45, ADI-15878, and ADI-15946. Together, these results provide the first structural insights into MLAV GP and identify immune evasion driven by structural and sequence divergence as a major challenge for pan-filovirus antibody development.
MLAV GP exhibits structural features that hinder binding of broadly neutralizing ebolavirus and marburgvirus antibodies, indicating molecular divergence that may affect cross-species immune interactions.
MLAV GP exhibits distinctive structural features in the Wing and HR1D regions... MR191, a broadly neutralizing marburgvirus antibody that targets the conserved NPC1 receptor-binding pocket in MLAV GP, nonetheless exhibits impaired neutralizing activity, likely due to shielding by the MLAV Cap.
Měnglà virus glycoprotein uses the same NPC1 receptor as Ebola and Marburg viruses, supporting molecular similarity that may facilitate cross-species transmission potential.
A recently identified bat-borne filovirus, Měnglà virus (MLAV), uses the same NPC1 receptor as EBOV and MARV, raising concerns about its potential cross-species transmission.
