COVID-19関連追加(202182日)ラムダ株について

SARS-CoV-2ラムダ株は高い感染性と免疫抵抗を示す】

Kimura I, …, Sato K. SARS-CoV-2 Lambda variant exhibits higher infectivity and immune resistance. bioRxiv. Posted July 28, 2021.

https://doi.org/10.1101/2021.07.28.454085.

Summary

SARS-CoV-2 ラムダは,現在,南米諸国で広がっているVOIである; しかし,そのウイルス学的特徴や進化的特徴はまだ明らかではない.本研究では,ラムダ株のスパイクタンパク質の感染性が高いことを明らかにし,その原因がT76IL452Qの変異にあることを明らかにした.RSYLTPGD246-253N変異は,ラムダスパイクタンパク質のN末端ドメイン(NTD)に存在する7-アミノ酸の欠失変異(a unique 7-amino-acid deletion mutationであり,中和抗体からの逃避に関与しているRSYLTPGD246-253N変異を持つ分離株の頻度の増加に伴い,ラムダ株が優位に拡大していることから,RSYLTPGD246-253N変異の挿入が,南米におけるラムダ株の大規模な感染拡大と密接に関連していることが示唆された.

Highlights

Lambda Sは高い感染性があり,T76IL452Qがこの特性を担っている.

Lambda Sはより感染増強抗体(infection-enhancing antibody)の影響を受けやすい.

RSYLTPGD246-253NL452QF490Sが抗ウイルス免疫に抵抗性を与える.

 

Figure1

 

 

Figure: Virological and immunological features of the Lambda variant.

(A) Pseudovirus assay. The HIV-1-based reporter viruses pseudotyped with the SARS-CoV-2 S proteins of the parental D614G (B.1), Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.427), Lambda (C.37) variants as well as the Lambda+N246-253RSYLTPGD derivative were prepared as described in STARMETHODS. The mutations in each variant are listed in Table S4. The pseudoviruses were inoculated into HOS-ACE2/TMPRSS2 cells at 1,000 ng HIV-1 p24 antigen, and the percentages of infectivity compared to the virus pseudotyped with parental S D614G are shown. (B) Neutralization assay. Neutralization assay was performed using the pseudoviruses with the S proteins of parental D614G, Lambda and Lambda+N246-253RSYLTPGD and 18 BNT162b2-vaccinated sera as described in STARMETHODS. The raw data are shown in Figure S2B. The number in the panel indicates the fold change of neutralization resistance of the Lambda S to the D614G S or the Lambda+N246-253RSYLTPGD derivative. (C and D) Structural insights of the mutations in the Lambda S. (C) Overlaid overviews of the crystal structure of SARS-CoV-2 S (PDB: 6ZGE, white) (Wrobel et al., 2020) and a homology model of the Lambda S (brown). The mutated residues in the Lambda S and the regions of NTD and RBD are indicated in red and blue. The squared regions are enlarged in (D). Mutated residues in the NTD (left) and RBD (right) of the Lambda S. The residues in the parental S and the Lambda S are indicated in red and black. (E) Pseudovirus assay. The HIV-1-based reporter viruses pseudotyped with the SARS-CoV-2 S proteins bearing respective mutations of the Lambda variant as well as the D614G S were prepared. The pseudoviruses were inoculated into HOS-ACE2/TMPRSS2 cells at 1,000 ng HIV-1 p24 antigen, and the percentages of infectivity compared to the virus pseudotyped with parental S D614G are shown. (F) Neutralization assay. Neutralization assay was performed using the pseudoviruses used in Figure 2B and 18 BNT162b2-vaccinated sera as described in STARMETHODS. The raw data are shown in Figure S2B. The number in the panel indicates the fold change of neutralization resistance to the D614G S. (G and H) Effect of monoclonal antibodies. (G) Antiviral effect of an NTD-targeting NAb clone 4A8 (Chi et al., 2020). (H) Enhancing effect of an EAb clone COV2-2490 (Liu et al., 2021c). The percentages of infectivity compared to the virus without antibodies are shown. In A, E and H, assays were performed in triplicate, and the average is shown with SD. Statistically significant differences (*, P < 0.05) versus the D614G S were determined by Student’s t test. In B and F, assays were performed in triplicate, and the average is shown with SD. Statistically significant differences were determined by Wilcoxon matched-pairs signed rank test. The P values are indicated in the figure. In G, assays were performed in quadruplicate, and the average is shown with SD. Statistically significant differences (*, P < 0.05) versus the value without antibody were determined by Student’s t test. NS, no statistical significance. See also Figure S2 and Table S4.

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