Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.

Several arenaviruses cause hemorrhagic fevers in humans with high case fatality rates. A vaccine named Candid#1 is available only against Junin virus (JUNV) in Argentina. Specific N-linked glycans on the arenavirus surface glycoprotein (GP) mask important epitopes and help the virus evade antibody r...

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Autores principales:	Takaaki Koma, Cheng Huang, Adrian Coscia, Steven Hallam, John T Manning, Junki Maruyama, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Jonathan Abraham, Slobodan Paessler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/61eb758c0e974ffaae50ec79a28710df
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spelling	oai:doaj.org-article:61eb758c0e974ffaae50ec79a28710df2021-12-02T19:59:40ZGlycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.1553-73661553-737410.1371/journal.ppat.1009356https://doaj.org/article/61eb758c0e974ffaae50ec79a28710df2021-03-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009356https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Several arenaviruses cause hemorrhagic fevers in humans with high case fatality rates. A vaccine named Candid#1 is available only against Junin virus (JUNV) in Argentina. Specific N-linked glycans on the arenavirus surface glycoprotein (GP) mask important epitopes and help the virus evade antibody responses. However the role of GPC glycans in arenavirus pathogenicity is largely unclear. In a lethal animal model of hemorrhagic fever-causing Machupo virus (MACV) infection, we found that a chimeric MACV with the ectodomain of GPC from Candid#1 vaccine was partially attenuated. Interestingly, mutations resulting in acquisition of N-linked glycans at GPC N83 and N166 frequently occurred in late stages of the infection. These glycosylation sites are conserved in the GPC of wild-type MACV, indicating that this is a phenotypic reversion for the chimeric MACV to gain those glycans crucial for infection in vivo. Further studies indicated that the GPC mutant viruses with additional glycans became more resistant to neutralizing antibodies and more virulent in animals. On the other hand, disruption of these glycosylation sites on wild-type MACV GPC rendered the virus substantially attenuated in vivo and also more susceptible to antibody neutralization, while loss of these glycans did not affect virus growth in cultured cells. We also found that MACV lacking specific GPC glycans elicited higher levels of neutralizing antibodies against wild-type MACV. Our findings revealed the critical role of specific glycans on GPC in arenavirus pathogenicity and have important implications for rational design of vaccines against this group of hemorrhagic fever-causing viruses.Takaaki KomaCheng HuangAdrian CosciaSteven HallamJohn T ManningJunki MaruyamaAida G WalkerMilagros MillerJeanon N SmithMichael PattersonJonathan AbrahamSlobodan PaesslerPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 3, p e1009356 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Takaaki Koma Cheng Huang Adrian Coscia Steven Hallam John T Manning Junki Maruyama Aida G Walker Milagros Miller Jeanon N Smith Michael Patterson Jonathan Abraham Slobodan Paessler Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.
description	Several arenaviruses cause hemorrhagic fevers in humans with high case fatality rates. A vaccine named Candid#1 is available only against Junin virus (JUNV) in Argentina. Specific N-linked glycans on the arenavirus surface glycoprotein (GP) mask important epitopes and help the virus evade antibody responses. However the role of GPC glycans in arenavirus pathogenicity is largely unclear. In a lethal animal model of hemorrhagic fever-causing Machupo virus (MACV) infection, we found that a chimeric MACV with the ectodomain of GPC from Candid#1 vaccine was partially attenuated. Interestingly, mutations resulting in acquisition of N-linked glycans at GPC N83 and N166 frequently occurred in late stages of the infection. These glycosylation sites are conserved in the GPC of wild-type MACV, indicating that this is a phenotypic reversion for the chimeric MACV to gain those glycans crucial for infection in vivo. Further studies indicated that the GPC mutant viruses with additional glycans became more resistant to neutralizing antibodies and more virulent in animals. On the other hand, disruption of these glycosylation sites on wild-type MACV GPC rendered the virus substantially attenuated in vivo and also more susceptible to antibody neutralization, while loss of these glycans did not affect virus growth in cultured cells. We also found that MACV lacking specific GPC glycans elicited higher levels of neutralizing antibodies against wild-type MACV. Our findings revealed the critical role of specific glycans on GPC in arenavirus pathogenicity and have important implications for rational design of vaccines against this group of hemorrhagic fever-causing viruses.
format	article
author	Takaaki Koma Cheng Huang Adrian Coscia Steven Hallam John T Manning Junki Maruyama Aida G Walker Milagros Miller Jeanon N Smith Michael Patterson Jonathan Abraham Slobodan Paessler
author_facet	Takaaki Koma Cheng Huang Adrian Coscia Steven Hallam John T Manning Junki Maruyama Aida G Walker Milagros Miller Jeanon N Smith Michael Patterson Jonathan Abraham Slobodan Paessler
author_sort	Takaaki Koma
title	Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.
title_short	Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.
title_full	Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.
title_fullStr	Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.
title_full_unstemmed	Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.
title_sort	glycoprotein n-linked glycans play a critical role in arenavirus pathogenicity.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/61eb758c0e974ffaae50ec79a28710df
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Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.

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