Homo sapiens
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PROVIDER: PRJNA127539 | ENA |
REPOSITORIES: ENA
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Project description: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.
2011-03-22 | E-GEOD-22319 | biostudies-arrayexpress
Project description: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.
2011-03-22 | GSE22319 | GEO
Project description:Although annual epidemics of seasonal influenza affect around 10% of the global population, current treatment options are limited and development of new antivirals is urgently needed. Here, using state-of-the-art quantitative phosphoproteomics, we reveal the unique phosphoproteome dynamics that occur in the host cell within minutes of influenza A virus (IAV) infection. Based on this virus-induced phosphorylation signature, we uncover cellular kinases required for the observed signalling pattern and find that inhibition of selected candidates, such as the G protein-coupled receptor kinase 2 (GRK2), leads to decreased IAV replication. As GRK2 has emerged as drug target in heart disease, we focus on its role in IAV infection and show that it is required for viral entry at the stage of uncoating. Replication of seasonal and pandemic IAVs is severely decreased by specific GRK2 inhibitors in primary human airway cultures and in an animal model. Our study reveals the IAV-induced changes to the cellular phosphoproteome and identifies GRK2 as a crucial node of the kinase network that enables IAV replication.
2018-09-13 | PXD009999 | Pride
Project description:Secondary bacterial infections (SBIs) exacerbate influenza-associated disease and mortality. Antimicrobial agents can reduce the severity of SBIs, but many have limited efficacy or cause adverse effects. Thus, new treatment strategies are needed. Kinetic models describing the infection process can help determine optimal therapeutic targets, the time scale on which a drug will be most effective, and how infection dynamics will change under therapy. To understand how different therapies perturb the dynamics of influenza infection and bacterial coinfection and to quantify the benefit of increasing a drug’s efficacy or targeting a different infection process, I analyzed data from mice treated with an antiviral, an antibiotic, or an immune modulatory agent with kinetic models. The results suggest that antivirals targeting the viral life cycle are most efficacious in the first 2 days of infection, potentially because of an improved immune response, and that increasing the clearance of infected cells is important for treatment later in the infection. For a coinfection, immunotherapy could control low bacterial loads with as little as 20 % efficacy, but more effective drugs would be necessary for high bacterial loads. Antibiotics targeting bacterial replication and administered 10 h after infection would require 100 % efficacy, which could be reduced to 40 % with prophylaxis. Combining immunotherapy with antibiotics could substantially increase treatment success. Taken together, the results suggest when and why some therapies fail, determine the efficacy needed for successful treatment, identify potential immune effects, and show how the regulation of underlying mechanisms can be used to design new therapeutic strategies.
Model is encoded by Ruby and submitted to BioModels by Ahmad Zyoud
2020-04-02 | MODEL1812040005 | BioModels
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the global pandemic of COVID-19, and no effective antiviral agents and vaccines are available. SARS-CoV-2 is classified as a biosafety level-3 (BLS-3) agent, impeding the basic research into its biology and the development of effective antivirals. Here, we described a safe cell culture system for production of transcription and replication-competent, biologically contained SARS-CoV-2 virus like particles (trVLP) that express a reporter gene (GFP) replacing viral nucleocapsid gene, which is required for viral genome packaging and virion assembly (SARS-CoV-2-GFP/N trVLP). The complete viral life cycle can be exclusively achieved and confined in the cells expressing SARS-CoV or SARS-CoV-2 N proteins in trans, but not MERS-CoV N. Additionally, genetic recombination of N supplied in trans into viral genome was not detected, as evidenced by sequence analysis after one-month serial passages in N-expressing Caco-2 cells. Moreover, Intein-mediated protein trans-splicing approach was utilized to split the viral N gene into two independent vectors, and the ligated viral N protein could function in trans to recapitulate entire viral life cycle, further securing the biosafety of this cell culture model. To prove the suitability of this system in antivirals discovery, we developed a 96-well format high throughput screening to identify salinomycin, monensin sodium and lycorine chloride exhibiting potent antiviral activities against SARS-CoV-2 infection. Collectively, we propose that this cell culture system based on Intein-N genetic complementation to produce SARS-CoV-2 trVLP provides a safe means to dissect the virus life cycle, and thus accelerate our understanding of virus biology, as well as for more applied uses such as the screening and development of novel antivirals, and thus represent powerful tools for SARS-CoV-2 study.
2020-12-03 | GSE162629 | GEO
Project description:High-Throughput Drug Screening identifies Pazopanib and Clofilium tosylate as effective treatments for malignant rhabdoid tumors
| PRJNA397908 | ENA
Project description:High-Throughput Drug Screening identifies Pazopanib and Clofilium tosylate as effective treatments for malignant rhabdoid tumors
| PRJNA384525 | ENA
Project description:Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing conserved influenza epitopes greatly outnumber antibodies reactive against variable epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors.
2022-02-09 | GSE196366 | GEO
Project description:Influenza A viruses (IAVs) are respiratory pathogens that represent a global concern due to their ability to cause seasonal epidemics and sporadic pandemics in the human population. Thus, a comprehensive understanding of IAV biology is essential in order to design effective antivirals. It is well established that entry of most IAVs begins through binding to cell surface sialic acid, however the identity of receptors that mediate virus internalization remains unclear. Here, we performed TurboID-based proximity labelling centered on epsin 1, a protein required for clathrin-mediated endocytosis of IAV, to uncover internalization receptors. By performing affinity-based purification of biotinylated proteins coupled to mass spectrometry, we identified 34 proteins proximal to epsin 1 during IAV infection. Therein we found 11 high-confidence STRING interactors for epsin 1 and 3 putative pro-viral host factors for IAV infection, validating our approach.
2025-05-08 | PXD058908 | Pride