Cargando…

Maximal interferon induction by influenza lacking NS1 is infrequent owing to requirements for replication and export

Influenza A virus exhibits high rates of replicative failure due to a variety of genetic defects. Most influenza virions cannot, when acting as individual particles, complete the entire viral life cycle. Nevertheless influenza is incredibly successful in the suppression of innate immune detection an...

Descripción completa

Detalles Bibliográficos
Autores principales: Vicary, Alison C., Mendes, Marisa, Swaminath, Sharmada, Lekbua, Asama, Reddan, Jack, Rodriguez, Zaida K., Russell, Alistair B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138204/
https://www.ncbi.nlm.nih.gov/pubmed/37068114
http://dx.doi.org/10.1371/journal.ppat.1010943
_version_ 1785032651568054272
author Vicary, Alison C.
Mendes, Marisa
Swaminath, Sharmada
Lekbua, Asama
Reddan, Jack
Rodriguez, Zaida K.
Russell, Alistair B.
author_facet Vicary, Alison C.
Mendes, Marisa
Swaminath, Sharmada
Lekbua, Asama
Reddan, Jack
Rodriguez, Zaida K.
Russell, Alistair B.
author_sort Vicary, Alison C.
collection PubMed
description Influenza A virus exhibits high rates of replicative failure due to a variety of genetic defects. Most influenza virions cannot, when acting as individual particles, complete the entire viral life cycle. Nevertheless influenza is incredibly successful in the suppression of innate immune detection and the production of interferons, remaining undetected in >99% of cells in tissue-culture models of infection. Notably, the same variation that leads to replication failure can, by chance, inactivate the major innate immune antagonist in influenza A virus, NS1. What explains the observed rarity of interferon production in spite of the frequent loss of this, critical, antagonist? By studying how genetic and phenotypic variation in a viral population lacking NS1 correlates with interferon production, we have built a model of the “worst-case” failure from an improved understanding of the steps at which NS1 acts in the viral life cycle to prevent the triggering of an innate immune response. In doing so, we find that NS1 prevents the detection of de novo innate immune ligands, defective viral genomes, and viral export from the nucleus, although only generation of de novo ligands appears absolutely required for enhanced detection of virus in the absence of NS1. Due to this, the highest frequency of interferon production we observe (97% of infected cells) requires a high level of replication in the presence of defective viral genomes with NS1 bearing an inactivating mutation that does not impact its partner encoded on the same segment, NEP. This is incredibly unlikely to occur given the standard variation found within a viral population, and would generally require direct, artificial, intervention to achieve at an appreciable rate. Thus from our study, we procure at least a partial explanation for the seeming contradiction between high rates of replicative failure and the rarity of the interferon response to influenza infection.
format Online
Article
Text
id pubmed-10138204
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-101382042023-04-28 Maximal interferon induction by influenza lacking NS1 is infrequent owing to requirements for replication and export Vicary, Alison C. Mendes, Marisa Swaminath, Sharmada Lekbua, Asama Reddan, Jack Rodriguez, Zaida K. Russell, Alistair B. PLoS Pathog Research Article Influenza A virus exhibits high rates of replicative failure due to a variety of genetic defects. Most influenza virions cannot, when acting as individual particles, complete the entire viral life cycle. Nevertheless influenza is incredibly successful in the suppression of innate immune detection and the production of interferons, remaining undetected in >99% of cells in tissue-culture models of infection. Notably, the same variation that leads to replication failure can, by chance, inactivate the major innate immune antagonist in influenza A virus, NS1. What explains the observed rarity of interferon production in spite of the frequent loss of this, critical, antagonist? By studying how genetic and phenotypic variation in a viral population lacking NS1 correlates with interferon production, we have built a model of the “worst-case” failure from an improved understanding of the steps at which NS1 acts in the viral life cycle to prevent the triggering of an innate immune response. In doing so, we find that NS1 prevents the detection of de novo innate immune ligands, defective viral genomes, and viral export from the nucleus, although only generation of de novo ligands appears absolutely required for enhanced detection of virus in the absence of NS1. Due to this, the highest frequency of interferon production we observe (97% of infected cells) requires a high level of replication in the presence of defective viral genomes with NS1 bearing an inactivating mutation that does not impact its partner encoded on the same segment, NEP. This is incredibly unlikely to occur given the standard variation found within a viral population, and would generally require direct, artificial, intervention to achieve at an appreciable rate. Thus from our study, we procure at least a partial explanation for the seeming contradiction between high rates of replicative failure and the rarity of the interferon response to influenza infection. Public Library of Science 2023-04-17 /pmc/articles/PMC10138204/ /pubmed/37068114 http://dx.doi.org/10.1371/journal.ppat.1010943 Text en © 2023 Vicary et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Vicary, Alison C.
Mendes, Marisa
Swaminath, Sharmada
Lekbua, Asama
Reddan, Jack
Rodriguez, Zaida K.
Russell, Alistair B.
Maximal interferon induction by influenza lacking NS1 is infrequent owing to requirements for replication and export
title Maximal interferon induction by influenza lacking NS1 is infrequent owing to requirements for replication and export
title_full Maximal interferon induction by influenza lacking NS1 is infrequent owing to requirements for replication and export
title_fullStr Maximal interferon induction by influenza lacking NS1 is infrequent owing to requirements for replication and export
title_full_unstemmed Maximal interferon induction by influenza lacking NS1 is infrequent owing to requirements for replication and export
title_short Maximal interferon induction by influenza lacking NS1 is infrequent owing to requirements for replication and export
title_sort maximal interferon induction by influenza lacking ns1 is infrequent owing to requirements for replication and export
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138204/
https://www.ncbi.nlm.nih.gov/pubmed/37068114
http://dx.doi.org/10.1371/journal.ppat.1010943
work_keys_str_mv AT vicaryalisonc maximalinterferoninductionbyinfluenzalackingns1isinfrequentowingtorequirementsforreplicationandexport
AT mendesmarisa maximalinterferoninductionbyinfluenzalackingns1isinfrequentowingtorequirementsforreplicationandexport
AT swaminathsharmada maximalinterferoninductionbyinfluenzalackingns1isinfrequentowingtorequirementsforreplicationandexport
AT lekbuaasama maximalinterferoninductionbyinfluenzalackingns1isinfrequentowingtorequirementsforreplicationandexport
AT reddanjack maximalinterferoninductionbyinfluenzalackingns1isinfrequentowingtorequirementsforreplicationandexport
AT rodriguezzaidak maximalinterferoninductionbyinfluenzalackingns1isinfrequentowingtorequirementsforreplicationandexport
AT russellalistairb maximalinterferoninductionbyinfluenzalackingns1isinfrequentowingtorequirementsforreplicationandexport