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TitleThe receptor binding domain of SARS-CoV-2 Omicron subvariants targets Siglec-9 to decrease its immunogenicity by preventing macrophage phagocytosis.
Journal, issue, pagesNat Immunol, Vol. 25, Issue 4, Page 622-632, Year 2024
Publish dateMar 7, 2024
AuthorsXin He / Xiantao Zhang / Bolin Wu / Jieyi Deng / Yongli Zhang / Airu Zhu / Yaochang Yuan / Yingtong Lin / Achun Chen / Jinzhu Feng / Xiumei Wang / Shijian Wu / Yingying Liu / Jie Liu / Yalin Wang / Rong Li / Chaofeng Liang / Quyu Yuan / Yu Liang / Qiannan Fang / Zhihui Xi / Wenjie Li / Liting Liang / Zhenglai Zhang / Hui Tang / Yi Peng / Changwen Ke / Xiancai Ma / Weibin Cai / Ting Pan / Bingfeng Liu / Kai Deng / Jun Chen / Jincun Zhao / Xuepeng Wei / Ran Chen / Yiwen Zhang / Hui Zhang /
PubMed AbstractThe development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a ...The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371-377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.
External linksNat Immunol / PubMed:38454157
MethodsEM (single particle)
Resolution2.9 - 2.92 Å
Structure data

37516

8wgv

EMDB-37516, PDB-8wgv:
BA.2(S375) Spike (S6P)/hACE2 complex
Method: EM (single particle) / Resolution: 2.92 Å

37517

8wgw

EMDB-37517, PDB-8wgw:
Local refinement of RBD-ACE2
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-ZN:
Unknown entry

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/HYDROLASE / Complex / VIRAL PROTEIN-HYDROLASE complex

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