Structure of the Lassa virus glycan shield provides a model for immunological resistance

Lassa virus is an Old World arenavirus endemic to West Africa that causes severe hemorrhagic fever. Vaccine development has focused on the envelope glycoprotein complex (GPC) that extends from the virion envelope. The often inadequate antibody immune response elicited by both vaccine and natural inf...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 115; no. 28; pp. 7320 - 7325
Main Authors Watanabe, Yasunori, Raghwani, Jayna, Allen, Joel D., Seabright, Gemma E., Li, Sai, Moser, Felipe, Huiskonen, Juha T., Strecker, Thomas, Bowden, Thomas A., Crispin, Max
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 10.07.2018
Subjects
Amino acids
Biological Sciences
Carbohydrates
Clusters
Disease resistance
Fever
Glycan
Glycoproteins
Glycosylation
Hemorrhage
Hemorrhagic fever
Immune response
Immune response (humoral)
Immune system
Immunology
Lassa virus - chemistry
Lassa virus - immunology
Oligosaccharides - chemistry
Oligosaccharides - immunology
Polysaccharides
Vaccine development
Vaccines
Viral Envelope Proteins - chemistry
Viral Envelope Proteins - immunology
Virions
Viruses
arenavirus
glycosylation
glycoprotein
Lassa virus
structure
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Summary:Lassa virus is an Old World arenavirus endemic to West Africa that causes severe hemorrhagic fever. Vaccine development has focused on the envelope glycoprotein complex (GPC) that extends from the virion envelope. The often inadequate antibody immune response elicited by both vaccine and natural infection has been, in part, attributed to the abundance of N-linked glycosylation on the GPC. Here, using a virus-like–particle system that presents Lassa virus GPC in a native-like context, we determine the composite population of each of the N-linked glycosylation sites presented on the trimeric GPC spike. Our analysis reveals the presence of underprocessed oligomannose-type glycans, which form punctuated clusters that obscure the proteinous surface of both the GP1 attachment and GP2 fusion glycoprotein subunits of the Lassa virus GPC. These oligomannose clusters are seemingly derived as a result of sterically reduced accessibility to glycan processing enzymes, and limited amino acid diversification around these sites supports their role protecting against the humoral immune response. Combined, our data provide a structure-based blueprint for understanding how glycans render the glycoprotein spikes of Lassa virus and other Old World arenaviruses immunologically resistant targets.
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Edited by Robert A. Lamb, HHMI and Northwestern University, Evanston, IL, and approved June 1, 2018 (received for review March 9, 2018)
Author contributions: Y.W., J.R., T.A.B., and M.C. designed research; Y.W., J.R., and S.L. performed research; S.L., F.M., J.T.H., and T.S. contributed new reagents/analytic tools; Y.W., J.R., J.D.A., G.E.S., T.A.B., and M.C. analyzed data; and Y.W., J.R., J.D.A., T.A.B., and M.C. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1803990115