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Volume 39 Issue 4
August 2024
    Citation: Jiao Guo, Yi Wan, Yang Liu, Xiaoying Jia, Siqi Dong, Gengfu Xiao, Wei Wang. Identification of residues in Lassa virus glycoprotein 1 involved in receptor switch .VIROLOGICA SINICA, 2024, 39(4) : 600-608.  http://dx.doi.org/10.1016/j.virs.2024.06.001
    shu

    Identification of residues in Lassa virus glycoprotein 1 involved in receptor switch

    • a. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China;

    • b. University of the Chinese Academy of Sciences, Beijing 100049, China;

    • c. The Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, School of Basic Medicine, Xi'an Medical University, Xi'an 710021, China

    • Corresponding author: Wei Wang, wangwei@wh.iov.cn
    • Received Date: 18 January 2024
      Accepted Date: 31 May 2024
      Available online: 06 June 2024
    • Lassa virus (LASV) is an enveloped, negative-sense RNA virus that causes Lassa hemorrhagic fever. Successful entry of LASV requires the viral glycoprotein 1 (GP1) to undergo a receptor switch from its primary receptor alpha-dystroglycan (α-DG) to its endosomal receptor lysosome-associated membrane protein 1 (LAMP1). A conserved histidine triad in LASV GP1 has been reported to be responsible for receptor switch. To test the hypothesis that other non-conserved residues also contribute to receptor switch, we constructed a series of mutant LASV GP1 proteins and tested them for binding to LAMP1. Four residues, L84, K88, L107, and H170, were identified as critical for receptor switch. Substituting any of the four residues with the corresponding lymphocytic choriomeningitis virus (LCMV) residue (L84 N, K88E, L10F, and H170S) reduced the binding affinity of LASV GP1 for LAMP1. Moreover, all mutations caused decreases in glycoprotein precursor (GPC)-mediated membrane fusion at both pH 4.5 and 5.2. The infectivity of pseudotyped viruses bearing either GPCL84N or GPCK88E decreased sharply in multiple cell types, while L107F and H170S had only mild effects on infectivity. Using biolayer light interferometry assay, we found that all four mutants had decreased binding affinity to LAMP1, in the order of binding affinity being L84 N > L107F > K88E > H170S. The four amino acid loci identified for the first time in this study have important reference significance for the in-depth investigation of the mechanism of receptor switching and immune escape of LASV occurrence and the development of reserve anti-LASV infection drugs.
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      Identification of residues in Lassa virus glycoprotein 1 involved in receptor switch

        Corresponding author: Wei Wang, wangwei@wh.iov.cn
      • a. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China;
      • b. University of the Chinese Academy of Sciences, Beijing 100049, China;
      • c. The Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, School of Basic Medicine, Xi'an Medical University, Xi'an 710021, China
      • Received Date: 18 January 2024
      • Accepted Date: 31 May 2024

      Abstract: Lassa virus (LASV) is an enveloped, negative-sense RNA virus that causes Lassa hemorrhagic fever. Successful entry of LASV requires the viral glycoprotein 1 (GP1) to undergo a receptor switch from its primary receptor alpha-dystroglycan (α-DG) to its endosomal receptor lysosome-associated membrane protein 1 (LAMP1). A conserved histidine triad in LASV GP1 has been reported to be responsible for receptor switch. To test the hypothesis that other non-conserved residues also contribute to receptor switch, we constructed a series of mutant LASV GP1 proteins and tested them for binding to LAMP1. Four residues, L84, K88, L107, and H170, were identified as critical for receptor switch. Substituting any of the four residues with the corresponding lymphocytic choriomeningitis virus (LCMV) residue (L84 N, K88E, L10F, and H170S) reduced the binding affinity of LASV GP1 for LAMP1. Moreover, all mutations caused decreases in glycoprotein precursor (GPC)-mediated membrane fusion at both pH 4.5 and 5.2. The infectivity of pseudotyped viruses bearing either GPCL84N or GPCK88E decreased sharply in multiple cell types, while L107F and H170S had only mild effects on infectivity. Using biolayer light interferometry assay, we found that all four mutants had decreased binding affinity to LAMP1, in the order of binding affinity being L84 N > L107F > K88E > H170S. The four amino acid loci identified for the first time in this study have important reference significance for the in-depth investigation of the mechanism of receptor switching and immune escape of LASV occurrence and the development of reserve anti-LASV infection drugs.

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