Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression signature-based screening identifies new broadly effective influenza antivirals

ABSTRACT: Classical antiviral therapy inhibit viral proteins and are subject to resistance. To counteract this emergence, alternative strategy has been developed that target cellular factors. We hypothesized that such approach could also be useful to identify broad antivirals. Influenza A virus was used as a model for viral diversity and need for therapy against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to identify a gene-expression signature associated with infection with different influenza A virus subtypes which could help to identify potential antiviral drugs with broad spectrum. Cellular gene expression response to infection with five different human and avian influenza viruses strains was analyzed and 300 genes were determined as differentially expressed between infected and non-infected samples. Strikingly, only a few genes were induced by infection and related to immune response. A more concise list was used to screen connectivity map, a database of drug-associated gene expression profiles, for molecules with inverse profiles than the signature of infection. We hypothesized that such compounds would induce an unfavorable cellular environment for influenza virus replication. Eight potential antivirals including ribavirin were identified, and six inhibited influenza viral growth in vitro. The new pandemic H1N1 virus, which was not used to define the gene expression signature of infection, was inhibited by five of the eight identified molecules, demonstrating that this strategy could help to identify broad spectrum antivirals. This is the first study showing that a gene expression based-screening can be used to identify antivirals. Such approaches could accelerate the drug discovery progress and could be extended to other pathogens. A549 (human lung epithelial cells) were infected with 5 different influenza A strains (A/New Caledonia/20/99 (H1N1), A/Moscow/10/99 (H3N2), A/Lyon/969/09 (H1N1 SOI-V), A/Turkey/582/2006 (H5N1), A/Finch/England/2051/94 (H5N2), and A/Chicken/Italy/2076/99 (H7N1)) or mock infected. Five independant replicates were done and hybridized on a different microarray. The overall design is thus composed of 5 mock samples, and 5x5 infected samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Julien Textoris

PROVIDER: E-GEOD-22319 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression signature-based screening identifies new broadly effective influenza a antivirals.

Josset Laurence L Textoris Julien J Loriod Béatrice B Ferraris Olivier O Moules Vincent V Lina Bruno B N'guyen Catherine C Diaz Jean-Jacques JJ Rosa-Calatrava Manuel M

PloS one 20101004 10

Classical antiviral therapies target viral proteins and are consequently subject to resistance. To counteract this limitation, alternative strategies have been developed that target cellular factors. We hypothesized that such an approach could also be useful to identify broad-spectrum antivirals. The influenza A virus was used as a model for its viral diversity and because of the need to develop therapies against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to i ...[more]

PMID: 20957181

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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.

Dataset Information

Gene expression signature-based screening identifies new broadly effective influenza antivirals

Publications

Gene expression signature-based screening identifies new broadly effective influenza a antivirals.

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