Cargando…

Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA

The interferon-induced myxovirus resistance protein A (MxA) is a potent restriction factor that prevents zoonotic infection from influenza A virus (IAV) subtype H7N9. Individuals expressing antivirally inactive MxA variants are highly susceptible to these infections. However, human-adapted IAVs have...

Descripción completa

Detalles Bibliográficos
Autores principales: Petric, Philipp P., King, Jacqueline, Graf, Laura, Pohlmann, Anne, Beer, Martin, Schwemmle, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695009/
https://www.ncbi.nlm.nih.gov/pubmed/36366429
http://dx.doi.org/10.3390/v14112331
_version_ 1784837949374857216
author Petric, Philipp P.
King, Jacqueline
Graf, Laura
Pohlmann, Anne
Beer, Martin
Schwemmle, Martin
author_facet Petric, Philipp P.
King, Jacqueline
Graf, Laura
Pohlmann, Anne
Beer, Martin
Schwemmle, Martin
author_sort Petric, Philipp P.
collection PubMed
description The interferon-induced myxovirus resistance protein A (MxA) is a potent restriction factor that prevents zoonotic infection from influenza A virus (IAV) subtype H7N9. Individuals expressing antivirally inactive MxA variants are highly susceptible to these infections. However, human-adapted IAVs have acquired specific mutations in the viral nucleoprotein (NP) that allow escape from MxA-mediated restriction but that have not been observed in MxA-sensitive, human H7N9 isolates. To date, it is unknown whether H7N9 can adapt to escape MxA-mediated restriction. To study this, we infected Rag2-knockout (Rag2(−/−)) mice with a defect in T and B cell maturation carrying a human MxA transgene (MxA(tg/−)Rag2(−/−)). In these mice, the virus could replicate for several weeks facilitating host adaptation. In MxA(tg/−)Rag2(−/−), but not in Rag2(−/−) mice, the well-described mammalian adaptation E627K in the viral polymerase subunit PB2 was acquired, but no variants with MxA escape mutations in NP were detected. Utilizing reverse genetics, we could show that acquisition of PB2 E627K allowed partial evasion from MxA restriction in MxA(tg/tg) mice. However, pretreatment with type I interferon decreased viral replication in these mice, suggesting that PB2 E627K is not a true MxA escape mutation. Based on these results, we speculate that it might be difficult for H7N9 to acquire MxA escape mutations in the viral NP. This is consistent with previous findings showing that MxA escape mutations cause severe attenuation of IAVs of avian origin.
format Online
Article
Text
id pubmed-9695009
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96950092022-11-26 Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA Petric, Philipp P. King, Jacqueline Graf, Laura Pohlmann, Anne Beer, Martin Schwemmle, Martin Viruses Article The interferon-induced myxovirus resistance protein A (MxA) is a potent restriction factor that prevents zoonotic infection from influenza A virus (IAV) subtype H7N9. Individuals expressing antivirally inactive MxA variants are highly susceptible to these infections. However, human-adapted IAVs have acquired specific mutations in the viral nucleoprotein (NP) that allow escape from MxA-mediated restriction but that have not been observed in MxA-sensitive, human H7N9 isolates. To date, it is unknown whether H7N9 can adapt to escape MxA-mediated restriction. To study this, we infected Rag2-knockout (Rag2(−/−)) mice with a defect in T and B cell maturation carrying a human MxA transgene (MxA(tg/−)Rag2(−/−)). In these mice, the virus could replicate for several weeks facilitating host adaptation. In MxA(tg/−)Rag2(−/−), but not in Rag2(−/−) mice, the well-described mammalian adaptation E627K in the viral polymerase subunit PB2 was acquired, but no variants with MxA escape mutations in NP were detected. Utilizing reverse genetics, we could show that acquisition of PB2 E627K allowed partial evasion from MxA restriction in MxA(tg/tg) mice. However, pretreatment with type I interferon decreased viral replication in these mice, suggesting that PB2 E627K is not a true MxA escape mutation. Based on these results, we speculate that it might be difficult for H7N9 to acquire MxA escape mutations in the viral NP. This is consistent with previous findings showing that MxA escape mutations cause severe attenuation of IAVs of avian origin. MDPI 2022-10-24 /pmc/articles/PMC9695009/ /pubmed/36366429 http://dx.doi.org/10.3390/v14112331 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Petric, Philipp P.
King, Jacqueline
Graf, Laura
Pohlmann, Anne
Beer, Martin
Schwemmle, Martin
Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA
title Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA
title_full Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA
title_fullStr Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA
title_full_unstemmed Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA
title_short Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA
title_sort increased polymerase activity of zoonotic h7n9 allows partial escape from mxa
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695009/
https://www.ncbi.nlm.nih.gov/pubmed/36366429
http://dx.doi.org/10.3390/v14112331
work_keys_str_mv AT petricphilippp increasedpolymeraseactivityofzoonotich7n9allowspartialescapefrommxa
AT kingjacqueline increasedpolymeraseactivityofzoonotich7n9allowspartialescapefrommxa
AT graflaura increasedpolymeraseactivityofzoonotich7n9allowspartialescapefrommxa
AT pohlmannanne increasedpolymeraseactivityofzoonotich7n9allowspartialescapefrommxa
AT beermartin increasedpolymeraseactivityofzoonotich7n9allowspartialescapefrommxa
AT schwemmlemartin increasedpolymeraseactivityofzoonotich7n9allowspartialescapefrommxa