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Maximal interferon induction in the absence of influenza NS1 is infrequent owing to requirements for replication and export

ABSTRACT: Influenza A virus exhibits high rates of replicative failure due to a variety of genetic defects. As such, most viral particles cannot complete the life cycle. However, despite this failure, this virus is incredibly successful in the suppression of innate immune detection and the production of interferons, succeeding at remaining undetected in >99% of cells in tissue-culture models of infection. As the same variation that leads to replication failure can, by chance, inactivate the major innate immune antagonist in influenza A virus, NS1, what features prevent these events from triggering massive amounts of interferon production? 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 lifecycle to prevent triggering of an innate immune response. In doing so, we find that NS1 prevents the detection of de novo innate immune ligands, and protects against both defective viral genomes, bearing large deletions, and viral products exported from the nucleus. Taken together, the highest level of stimulation we observe ( 97% of infected cells), requires a high level of replication in the presence of defective viral genomes with NS1 and NS1 alone from the NS segment bearing an inactivating mutation. This is incredibly unlikely to occur within 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.

ORGANISM(S): Canis lupus familiaris Homo sapiens Influenza A virus (A/WSN/1933(H1N1))

PROVIDER: GSE215914 | GEO | 2022/10/27

REPOSITORIES: GEO

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Project description:Fribourg2014 - Dynamics of viral antagonism and innate immune response (H1N1 influenza A virus - Cal/09) The dynamics of the interplay between the viral antagonism and the innate immune response has been studied using modelling approaches. The responses of human monocyte-derived dendritic cells infected by two influenza A H1N1 strains (the pandemic swine-origin A/California/4/2009 (Cal/09) and the seasonal A/New Caledonia/20/1999 (NC/99)) that have different clinical outcomes have been modelled. From the time course gene expression measurements of a set of selected genes, the dynamic features of viral antagonism and innate immune response are extracted. It is found that the strength and the time scale of action of viral antagonism is significantly different between the two viruses. This model describes the viral infection by seasonal Cal/09. This model is described in the article: Model of influenza A virus infection: Dynamics of viral antagonism and innate immune response. Fribourg M, Hartmann B, Schmolke M, Marjanovic N, Albrecht RA, García-Sastre A, Sealfon SC, Jayaprakash C, Hayot F. J Theor Biol. 2014 Mar 2;351C:47-57. Abstract: Viral antagonism of host responses is an essential component of virus pathogenicity. The study of the interplay between immune response and viral antagonism is challenging due to the involvement of many processes acting at multiple time scales. Here we develop an ordinary differential equation model to investigate the early, experimentally measured, responses of human monocyte-derived dendritic cells to infection by two H1N1 influenza A viruses of different clinical outcomes: pandemic A/California/4/2009 and seasonal A/New Caledonia/20/1999. Our results reveal how the strength of virus antagonism, and the time scale over which it acts to thwart the innate immune response, differs significantly between the two viruses, as is made clear by their impact on the temporal behavior of a number of measured genes. The model thus sheds light on the mechanisms that underlie the variability of innate immune responses to different H1N1 viruses. This model is hosted on BioModels Database and identified by: MODEL1403310002. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Fribourg2014 - Dynamics of viral antagonism and innate immune response (H1N1 influenza A virus - NC/99) The dynamics of the interplay between the viral antagonism and the innate immune response has been studied using modelling approaches. The responses of human monocyte-derived dendritic cells infected by two influenza A H1N1 strains (the pandemic swine-origin A/California/4/2009 (Cal/09) and the seasonal A/New Caledonia/20/1999 (NC/99)) that have different clinical outcomes have been modelled. From the time course gene expression measurements of a set of selected genes, the dynamic features of viral antagonism and innate immune response are extracted. It is found that the strength and the time scale of action of viral antagonism is significantly different between the two viruses. This model describes the viral infection by seasonal NC/99. This model is described in the article: Model of influenza A virus infection: Dynamics of viral antagonism and innate immune response. Fribourg M, Hartmann B, Schmolke M, Marjanovic N, Albrecht RA, García-Sastre A, Sealfon SC, Jayaprakash C, Hayot F. J Theor Biol. 2014 Mar 2;351C:47-57. Abstract: Viral antagonism of host responses is an essential component of virus pathogenicity. The study of the interplay between immune response and viral antagonism is challenging due to the involvement of many processes acting at multiple time scales. Here we develop an ordinary differential equation model to investigate the early, experimentally measured, responses of human monocyte-derived dendritic cells to infection by two H1N1 influenza A viruses of different clinical outcomes: pandemic A/California/4/2009 and seasonal A/New Caledonia/20/1999. Our results reveal how the strength of virus antagonism, and the time scale over which it acts to thwart the innate immune response, differs significantly between the two viruses, as is made clear by their impact on the temporal behavior of a number of measured genes. The model thus sheds light on the mechanisms that underlie the variability of innate immune responses to different H1N1 viruses. This model is hosted on BioModels Database and identified by: MODEL1403310001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Maximal interferon induction in the absence of influenza NS1 is infrequent owing to requirements for replication and export

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