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IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization

The disease severity of influenza is highly variable in humans, and one genetic determinant behind these differences is the IFITM3 gene. As an effector of the interferon response, IFITM3 potently blocks cytosolic entry of influenza A virus (IAV). Here, we reveal a novel level of inhibition by IFITM3...

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Autores principales: Lanz, Caroline, Schotsaert, Michael, Magnus, Carsten, Karakus, Umut, Hunziker, Annika, Sempere Borau, Milagros, Martínez-Romero, Carles, Spieler, Eva E., Günther, Sira C., Moritz, Eva, Hale, Benjamin G., Trkola, Alexandra, García-Sastre, Adolfo, Stertz, Silke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072448/
https://www.ncbi.nlm.nih.gov/pubmed/33882122
http://dx.doi.org/10.1084/jem.20200303
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author Lanz, Caroline
Schotsaert, Michael
Magnus, Carsten
Karakus, Umut
Hunziker, Annika
Sempere Borau, Milagros
Martínez-Romero, Carles
Spieler, Eva E.
Günther, Sira C.
Moritz, Eva
Hale, Benjamin G.
Trkola, Alexandra
García-Sastre, Adolfo
Stertz, Silke
author_facet Lanz, Caroline
Schotsaert, Michael
Magnus, Carsten
Karakus, Umut
Hunziker, Annika
Sempere Borau, Milagros
Martínez-Romero, Carles
Spieler, Eva E.
Günther, Sira C.
Moritz, Eva
Hale, Benjamin G.
Trkola, Alexandra
García-Sastre, Adolfo
Stertz, Silke
author_sort Lanz, Caroline
collection PubMed
description The disease severity of influenza is highly variable in humans, and one genetic determinant behind these differences is the IFITM3 gene. As an effector of the interferon response, IFITM3 potently blocks cytosolic entry of influenza A virus (IAV). Here, we reveal a novel level of inhibition by IFITM3 in vivo: We show that incorporation of IFITM3 into IAV particles competes with incorporation of viral hemagglutinin (HA). Decreased virion HA levels did not reduce infectivity, suggesting that high HA density on IAV virions may be an antagonistic strategy used by the virus to prevent direct inhibition. However, we found that IFITM3-mediated reduction in HA content sensitizes IAV to antibody-mediated neutralization. Mathematical modeling predicted that this effect decreases and delays peak IAV titers, and we show that, indeed, IFITM3-mediated sensitization of IAV to antibody-mediated neutralization impacts infection outcome in an in vivo mouse model. Overall, our data describe a previously unappreciated interplay between the innate effector IFITM3 and the adaptive immune response.
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spelling pubmed-80724482021-12-07 IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization Lanz, Caroline Schotsaert, Michael Magnus, Carsten Karakus, Umut Hunziker, Annika Sempere Borau, Milagros Martínez-Romero, Carles Spieler, Eva E. Günther, Sira C. Moritz, Eva Hale, Benjamin G. Trkola, Alexandra García-Sastre, Adolfo Stertz, Silke J Exp Med Article The disease severity of influenza is highly variable in humans, and one genetic determinant behind these differences is the IFITM3 gene. As an effector of the interferon response, IFITM3 potently blocks cytosolic entry of influenza A virus (IAV). Here, we reveal a novel level of inhibition by IFITM3 in vivo: We show that incorporation of IFITM3 into IAV particles competes with incorporation of viral hemagglutinin (HA). Decreased virion HA levels did not reduce infectivity, suggesting that high HA density on IAV virions may be an antagonistic strategy used by the virus to prevent direct inhibition. However, we found that IFITM3-mediated reduction in HA content sensitizes IAV to antibody-mediated neutralization. Mathematical modeling predicted that this effect decreases and delays peak IAV titers, and we show that, indeed, IFITM3-mediated sensitization of IAV to antibody-mediated neutralization impacts infection outcome in an in vivo mouse model. Overall, our data describe a previously unappreciated interplay between the innate effector IFITM3 and the adaptive immune response. Rockefeller University Press 2021-04-21 /pmc/articles/PMC8072448/ /pubmed/33882122 http://dx.doi.org/10.1084/jem.20200303 Text en © 2021 Lanz et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Lanz, Caroline
Schotsaert, Michael
Magnus, Carsten
Karakus, Umut
Hunziker, Annika
Sempere Borau, Milagros
Martínez-Romero, Carles
Spieler, Eva E.
Günther, Sira C.
Moritz, Eva
Hale, Benjamin G.
Trkola, Alexandra
García-Sastre, Adolfo
Stertz, Silke
IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
title IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
title_full IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
title_fullStr IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
title_full_unstemmed IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
title_short IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
title_sort ifitm3 incorporation sensitizes influenza a virus to antibody-mediated neutralization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072448/
https://www.ncbi.nlm.nih.gov/pubmed/33882122
http://dx.doi.org/10.1084/jem.20200303
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