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Effects of N-linked glycan of Lassa Virus Envelope Glycoprotein on the Immune Response

By Xueqin Zhu, Yang Liu, Jiao Guo, Zonglin Wang, Junyuan Cao, Gengfu Xiao, Wei Wang

Posted 30 Sep 2020
bioRxiv DOI: 10.1101/2020.09.29.319855

Lassa virus (LASV) belongs to the Mammarenavirus genus (family Arenaviridae) and causes severe hemorrhagic fever in humans. The glycoprotein precursor (GPC) contains eleven N-linked glycans that play essential roles in GPC functionalities such as cleavage, transport, receptor recognition, epitope shielding, and immune response. We used three mutagenesis strategies to abolish the individual glycan chains on the GPC and found that all three mutations led to cleavage inefficiency on the 2nd, 5th, and 8th glycosylation motifs. To evaluate N to Q mutagenesis for further research, it was found that deletion of the 2nd and 8th glycans completely inhibited the infectivity. We further investigated the role of glycans on GPC-mediated immune response by DNA immunization of mice. Deletion of the individual 1st, 3rd, 5th and 6th glycans significantly enhanced the proportion of effector CD4+ cells, whereas deletion of the 1st, 2nd, 3rd, 4th 5th, 6th, and 9th glycans enhanced the proportion of CD8+ effector T cells. Deletion of specific glycans improves the Th1-type immune response, and abolishment of glycan on GPC generally increases the antibody titer to the glycan-deficient GPC. However, the antibodies from either the mutant or WT GPC-immunized mice show little neutralization effect on wild-type LASV. The glycan residues on GPC provide an immune shield for the virus, and thus represent a target for the design and development of a vaccine. Importance At present, there are no Food and Drug Administration-approved drugs or vaccines specific for LASV. Similar to other enveloped viruses with a heavy glycan shield, the N-linked glycans of LASV make it difficult for effector T cells and neutralization antibodies to access the glycoprotein epitope. In this study, we evaluated the effect of the individual glycan chains on GPC-mediated immune response, and found that deletion of the glycan improves the proportion of effector T cells, improving the Th1-type immune response, and increasing the antibody titer to the WT and mutant GPC, which may be beneficial to vaccine design and development.

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