Science reveals the structural basis for human-derived antibodies to synergistically neutralize Congo hemorrhagic fever virus

Written | Edited by Qi | Enzymatic Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is an endemic disease in Africa, Asia and Europe.
It is transmitted through tick bites or contact with the body fluids of viremic animals or patients
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Although asymptomatic in most vertebrates, it can cause symptoms such as bleeding, myalgia, and high fever in humans, eventually leading to the death of about 30% of confirmed cases
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CCHFV infects host cells with its envelope glycoproteins Gn and Gc.
After they are cleaved from the polyglycoprotein precursor by the host protease, a locally ordered heterodimer lattice is formed on the surface of the virus [1]
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After entering the target cell through receptor-mediated endocytosis, the acidic environment of the endosome triggers the dissociation of the Gn/Gc heterodimer and the surface lattice, and then the Gc conformation changes to a hairpin trimer to drive membrane fusion
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Like most Bunia viruses, CCHFV Gc is predicted to be a class II membrane fusion protein, and it is the only known target of CCHFV neutralizing antibodies [2, 3]
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However, there is still a lack of structural information on antibody-mediated neutralization mechanisms
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On November 18, 2021, the Jason S.
McLellan team from the University of Texas at Austin and Felix A.
Rey from the Structural Virology Group of the Pasteur Institute jointly published an article titled Structural in Science.
Basis of synergistic neutralization of Crimean Congo hemorrhagic fever virus by human antibodies.
This study describes the structure of Gc before fusion and forms a trimer after fusion, revealing the previously reported neutralization mechanism of anti-CCHFV antibodies, and is for the development of CCHFV Specific treatment strategies provide the necessary molecular basis
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Among the human monoclonal antibodies (Mab) targeting CCHFV Gc, ADI-36121 and ADI-37801 showed a synergistic effect in the test [3]
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The team respectively determined the X-ray structure of the CCHFV Gc fusion trimer and monomer Gc bound to two antibody Fabs (Figure 1).
Among them, ADI-36121 Fab binds to domain II, and ADI-37801 Fab binds to Gc's host-membrane insertion surface (host-membrane insertion surface, HMIS)
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Figure 1.
The structure of CCHFV Gc.
Next, the team established a detection method to track the syncytium formation of cells expressing CCHFV glycoprotein on their surface after low pH treatment to test the residue pairs Gc selected through structural analysis The function plays an important role, and the alanine replacement of two conserved residues at the hairpin junction after fusion (domain I and III interface) eliminates the cell fusion triggered by low pH
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Importantly, structural analysis showed that the residues exposed at the HMIS constitute the epitope of ADI-37801, and the residues essential for membrane fusion such as Trp1191, Trp1197 and Trp1199 are part of the epitope of ADI-37801, suggesting ADI-37801 suppresses the insertion of Gc into the endosomal membrane by masking the fusion ring of Gc
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The structure comparison shows that another antibody ADI-36121 epitope is completely buried in the trimer binding interface after the trimer is formed after Gc fusion (Figure 2)
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To prove this, the team used biolayer interferometry (BLI) to compare the binding ability of antibodies with recombinant soluble Gc monomers and trimers.
The results showed that the affinity of ADI-36121 to monomers was relative to that of trimers.
It is about 200 times higher, suggesting that ADI-36121 can neutralize CCHFV by blocking the homotrimerization of Gc in the endosome and preventing membrane fusion
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Figure 2.
The ADI-36121 epitope is buried in the trimer interface of the hairpin after fusion.
Previous studies have been based on the Gc homology model of the MPRLV Gc structure to assign CCHFV neutralizing antibodies to six different antigenic sites [3], In this study, the team further mapped these sites to HMIS or other epitopes buried in the Gc-driven membrane fusion process, revealing the neutralization mechanism of these two antibodies
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Specifically, position 1 maps to the cd loop, which is conserved between CCHFV strains and members of the genus Nerovirus; positions 2-4 are located at the Gc trimer core interface after fusion, the most effective neutralizing antibody ADI36121 targets site 3 and also shows highly effective cross-clade neutralization, which makes it an important candidate for clinical drug development
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Positions 5 and 6 map to domains I and III, respectively, and domain III contains more sequence polymorphisms in the CCHFV strain.
Therefore, compared with other positions, the antibody against position 6 is in the cross-clade And the effect may be more limited
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In summary, this study shows through structural analysis that the antibodies ADI-37801 and ADI-36121 exhibit a synergistic mechanism in the neutralization test.
ADI36121 binding indirectly affects the Gc fusion ring dynamics through the disturbance of the glycoprotein surface lattice.
Makes HMIS more exposed, which makes ADI37801 easier to identify its epitope
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Therefore, the combination with ADI-36121 should also expand the reactivity of ADI-37801 with various CCHFV strains, making these two antibodies powerful candidates for therapeutic antibody mixtures
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Original link: http://doi.
org/10.
1126/science.
abl6502 Platemaker: Eleven References 1.
P.
Guardado-Calvo, FA Rey, The Envelope Proteins of the Bunyavirales.
Adv.
Virus Res.
98, 83– 118 (2017).
doi:10.
1016/bs.
aivir.
2017.
02.
002 Medline2.
RJG Hulswit, GC Paesen, TA Bowden, X.
Shi, Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure.
Viruses 13, 353 (2021).
doi:10.
3390/v13020353 Medline3.
JM Fels, DP Maurer, AS Herbert, AS Wirchnianski, O.
Vergnolle, RW Cross, DM Abelson, CL Moyer, AK Mishra, JT Aguilan, AI Kuehne, NT Pauli, RR Bakken , EK Nyakatura, J.
Hellert, G.
Quevedo, L.
Lobel, S.
Balinandi, JJ Lutwama, L.
Zeitlin, TW Geisbert, FA Rey, S.
Sidoli, JS McLellan, JR Lai, ZA Bornholdt, JM Dye, LM Walker, K.
Chandran,Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever.
Cell 184, 3486–3501.
e21 (2021).
doi:10.
1016/j.
cell.
2021.
05.
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