Dromedary camels as a natural source of neutralizing nanobodies against SARS-CoV-2
Lotfi Chouchane, … , Murugan Subramanian, Jingxuan Shan
Lotfi Chouchane, … , Murugan Subramanian, Jingxuan Shan
Published February 2, 2021
Citation Information: JCI Insight. 2021;6(5):e145785. https://doi.org/10.1172/jci.insight.145785.
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Research Article COVID-19

Dromedary camels as a natural source of neutralizing nanobodies against SARS-CoV-2

Abstract

The development of prophylactic and therapeutic agents for coronavirus disease 2019 (COVID-19) is a current global health priority. Here, we investigated the presence of cross-neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in dromedary camels that were Middle East respiratory syndrome coronavirus (MERS-CoV) seropositive but MERS-CoV free. The tested 229 dromedaries had anti–MERS-CoV camel antibodies with variable cross-reactivity patterns against SARS-CoV-2 proteins, including the S trimer and M, N, and E proteins. Using SARS-CoV-2 competitive immunofluorescence immunoassays and pseudovirus neutralization assays, we found medium-to-high titers of cross-neutralizing antibodies against SARS-CoV-2 in these animals. Through linear B cell epitope mapping using phage immunoprecipitation sequencing and a SARS-CoV-2 peptide/proteome microarray, we identified a large repertoire of Betacoronavirus cross-reactive antibody specificities in these dromedaries and demonstrated that the SARS-CoV-2–specific VHH antibody repertoire is qualitatively diverse. This analysis revealed not only several SARS-CoV-2 epitopes that are highly immunogenic in humans, including a neutralizing epitope, but also epitopes exclusively targeted by camel antibodies. The identified SARS-CoV-2 cross-neutralizing camel antibodies are not proposed as a potential treatment for COVID-19. Rather, their presence in nonimmunized camels supports the development of SARS-CoV-2 hyperimmune camels, which could be a prominent source of therapeutic agents for the prevention and treatment of COVID-19.

Authors

Lotfi Chouchane, Jean-Charles Grivel, Elmoubasher Abu Baker Abd Farag, Igor Pavlovski, Selma Maacha, Abbirami Sathappan, Hamad Eid Al-Romaihi, Sirin W.J. Abuaqel, Manar Mahmoud Ahmad Ata, Aouatef Ismail Chouchane, Sami Remadi, Najeeb Halabi, Arash Rafii, Mohammed H. Al-Thani, Nico Marr, Murugan Subramanian, Jingxuan Shan

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Figure 4

Linear epitope mapping of virus antibodies by VirScan.

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Linear epitope mapping of virus antibodies by VirScan. (A) The distribut...
(A) The distribution of top 20 VirScan hit enrichments among 56 camel sera. (B) The hit enrichments of S and N proteins of all Betacoronavirus among 56 camel sera. (C–E) Sequence alignment and protein conformation analysis of S protein. (C) Schematic structure and VirScan hits of S protein. Red represents hits of MERS-CoV, and blue represents hits of SARS-CoV. (D) Overview of multiple alignment of antigenic regions of SARS-CoV-2, SARS-CoV, and MERS-CoV. Structure: helix (H; pink probability gradient), sheet (E; blue probability gradient), and coil (C, orange probability gradient) predicted using NetsurfP. Surface: buried(B)/exposed(E) from NetsurfP’s default threshold. Orange gradient illustrates predicted relative surface accessibility. ***E value < 0.001, ****E value < 0.0001, calculated by MEME. (E) S trimer of SARS-CoV-2, SARS-CoV, and MERS-CoV in the prefusion conformation. The view of conformation is observed from 2 directions, and the homology sequence position on protein is labeled by the corresponding colors. (F–H) Sequence alignment and protein conformation analysis of N protein. (F) Schematic structure and VirScan hits of N protein. (G) Overview of multiple alignment of antigenic regions of SARS-CoV-2, SARS-CoV, and MERS-CoV. (H) Monomer of the N protein of SARS-CoV-2 in the prefusion conformation. The structures of SARS-CoV and SARS-CoV-2 spanning region 2 in D and the structures of SARS-CoV and MERS-CoV spanning regions 1, 2, and 3 in G are not available in Protein Data Bank (PDB). Highlighted regions are shown as surfaces, whereas the protein backbone is shown as a cartoon. S proteins are represented using PDB codes 6ACC (SARS-CoV-2), 5X59 (MERS-CoV), and 6VXX (SARS-CoV-2), and N protein with PDB codes 6Y13 and 6YUN (SARS-CoV-2).