Faculty Opinions recommendation of Genome-wide fitness profiling reveals adaptations required by Haemophilus in coinfection with influenza A virus in the murine lung.

2013 ◽  
Author(s):  
Richard Webby
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Murine Lung ◽  
Genome Wide

scholarly journals Cathepsin W Is Required for Escape of Influenza A Virus from Late Endosomes

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Thomas O. Edinger ◽  
Marie O. Pohl ◽  
Emilio Yángüez ◽  
Silke Stertz
Keyword(s):  
Influenza Virus ◽  
Rna Interference ◽  
Influenza A Virus ◽  
Proteolytic Activity ◽  
Influenza A ◽  
Antiviral Drugs ◽  
Influenza Viruses ◽  
Late Endosomes ◽  
Genome Wide ◽  
Cathepsin W

ABSTRACT Human cathepsin W (CtsW) is a cysteine protease, which was identified in a genome-wide RNA interference (RNAi) screen to be required for influenza A virus (IAV) replication. In this study, we show that reducing the levels of expression of CtsW reduces viral titers for different subtypes of IAV, and we map the target step of CtsW requirement to viral entry. Using a set of small interfering RNAs (siRNAs) targeting CtsW, we demonstrate that knockdown of CtsW results in a decrease of IAV nucleoprotein accumulation in the nuclei of infected cells at 3 h postinfection. Assays specific for the individual stages of IAV entry further show that attachment, internalization, and early endosomal trafficking are not affected by CtsW knockdown. However, we detected impaired escape of viral particles from late endosomes in CtsW knockdown cells. Moreover, fusion analysis with a dual-labeled influenza virus revealed a significant reduction in fusion events, with no detectable impact on endosomal pH, suggesting that CtsW is required at the stage of viral fusion. The defect in IAV entry upon CtsW knockdown could be rescued by ectopic expression of wild-type CtsW but not by the expression of a catalytically inactive mutant of CtsW, suggesting that the proteolytic activity of CtsW is required for successful entry of IAV. Our results establish CtsW as an important host factor for entry of IAV into target cells and suggest that CtsW could be a promising target for the development of future antiviral drugs. IMPORTANCE Increasing levels of resistance of influenza viruses to available antiviral drugs have been observed. Development of novel treatment options is therefore of high priority. In parallel to the classical approach of targeting viral enzymes, a novel strategy is pursued: cell-dependent factors of the virus are identified with the aim of developing small-molecule inhibitors against a cellular target that the virus relies on. For influenza A virus, several genome-wide RNA interference (RNAi) screens revealed hundreds of potential cellular targets. However, we have only limited knowledge on how these factors support virus replication, which would be required for drug development. We have characterized cathepsin W, one of the candidate factors, and found that cathepsin W is required for escape of influenza virus from the late endosome. Importantly, this required the proteolytic activity of cathepsin W. We therefore suggest that cathepsin W could be a target for future host cell-directed antiviral therapies.

scholarly journals Reassortment Network of Influenza A Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Xingfei Gong ◽  
Mingda Hu ◽  
Wei Chen ◽  
Haoyi Yang ◽  
Boqian Wang ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Phylogenetic Trees ◽  
Minimum Spanning Tree ◽  
Comprehensive Understanding ◽  
Genome Sequences ◽  
Genetic Characteristics ◽  
Time Period ◽  
Genome Wide ◽  
History Of

Influenza A virus (IAV) genomes are composed of eight single-stranded RNA segments. Genetic exchange through reassortment of the segmented genomes often endows IAVs with new genetic characteristics, which may affect transmissibility and pathogenicity of the viruses. However, a comprehensive understanding of the reassortment history of IAVs remains lacking. To this end, we assembled 40,296 whole-genome sequences of IAVs for analysis. Using a new clustering method based on Mean Pairwise Distances in the phylogenetic trees, we classified each segment of IAVs into clades. Correspondingly, reassortment events among IAVs were detected by checking the segment clade compositions of related genomes under specific environment factors and time period. We systematically identified 1,927 possible reassortment events of IAVs and constructed their reassortment network. Interestingly, minimum spanning tree of the reassortment network reproved that swine act as an intermediate host in the reassortment history of IAVs between avian species and humans. Moreover, reassortment patterns among related subtypes constructed in this study are consistent with previous studies. Taken together, our genome-wide reassortment analysis of all the IAVs offers an overview of the leaping evolution of the virus and a comprehensive network representing the relationships of IAVs.

scholarly journals Genome-wide CRISPR screen identifies host dependency factors for influenza A virus infection

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Bo Li ◽  
Sara M. Clohisey ◽  
Bing Shao Chia ◽  
Bo Wang ◽  
Ang Cui ◽  
...  
Keyword(s):  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Meta Analysis ◽  
Host Factors ◽  
Validation Data ◽  
Genome Wide ◽  
A Genome ◽  
Crispr Screen ◽  
Influenza A Virus Infection

AbstractHost dependency factors that are required for influenza A virus infection may serve as therapeutic targets as the virus is less likely to bypass them under drug-mediated selection pressure. Previous attempts to identify host factors have produced largely divergent results, with few overlapping hits across different studies. Here, we perform a genome-wide CRISPR/Cas9 screen and devise a new approach, meta-analysis by information content (MAIC) to systematically combine our results with prior evidence for influenza host factors. MAIC out-performs other meta-analysis methods when using our CRISPR screen as validation data. We validate the host factors, WDR7, CCDC115 and TMEM199, demonstrating that these genes are essential for viral entry and regulation of V-type ATPase assembly. We also find that CMTR1, a human mRNA cap methyltransferase, is required for efficient viral cap snatching and regulation of a cell autonomous immune response, and provides synergistic protection with the influenza endonuclease inhibitor Xofluza.

scholarly journals A Host Susceptibility Gene, DR1, Facilitates Influenza A Virus Replication by Suppressing Host Innate Immunity and Enhancing Viral RNA Replication

2015 ◽  
Vol 89 (7) ◽  
pp. 3671-3682 ◽  
Author(s):  
Shih-Feng Hsu ◽  
Wen-Chi Su ◽  
King-Song Jeng ◽  
Michael M. C. Lai
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Susceptibility Gene ◽  
Influenza Virus Infection ◽  
Rna Replication ◽  
Viral Rna ◽  
Host Susceptibility ◽  
Viral Rdrp ◽  
Genome Wide ◽  
A Genome

ABSTRACTInfluenza A virus (IAV) depends on cellular factors to complete its replication cycle; thus, investigation of the factors utilized by IAV may facilitate antiviral drug development. To this end, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNA interference (RNAi) screen. Knockdown (KD) of DR1 resulted in reductions of viral RNA and protein production, demonstrating that DR1 acts as a positive host factor in IAV replication. Genome-wide transcriptomic analysis showed that there was a strong induction of interferon-stimulated gene (ISG) expression after prolonged DR1 KD. We found that beta interferon (IFN-β) was induced by DR1 KD, thereby activating the JAK-STAT pathway to turn on ISG expression, which led to a strong inhibition of IAV replication. This result suggests that DR1 in normal cells suppresses IFN induction, probably to prevent undesired cytokine production, but that this suppression may create a milieu that favors IAV replication once cells are infected. Furthermore, biochemical assays of viral RNA replication showed that DR1 KD suppressed viral RNA replication. We also showed that DR1 associated with all three subunits of the viral RNA-dependent RNA polymerase (RdRp) complex, indicating that DR1 may interact with individual components of the viral RdRp complex to enhance viral RNA replication. Thus, DR1 may be considered a novel host susceptibility gene for IAV replication via a dual mechanism, not only suppressing the host defense to indirectly favor IAV replication but also directly facilitating viral RNA replication.IMPORTANCEInvestigations of virus-host interactions involved in influenza A virus (IAV) replication are important for understanding viral pathogenesis and host defenses, which may manipulate influenza virus infection or prevent the emergence of drug resistance caused by a high error rate during viral RNA replication. For this purpose, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen as a positive regulator in IAV replication. In the current studies, we showed that DR1 suppressed the gene expression of a large set of host innate immunity genes, which indirectly facilitated IAV replication in the event of IAV infection. Besides this scenario, DR1 also directly enhanced the viral RdRp activity, likely through associating with individual components of the viral RdRp complex. Thus, DR1 represents a novel host susceptibility gene for IAV replication via multiple functions, not only suppressing the host defense but also enhancing viral RNA replication. DR1 may be a potential target for drug development against influenza virus infection.

scholarly journals Genome-wide screens - a systematic approach to redefine the influenza A virus-host crosstalk

2014 ◽  
Vol 2 (1) ◽  
pp. 2 ◽  
Author(s):  
Adarsh K Mayank ◽  
Shipra Sharma ◽  
Ravi K Deshwal ◽  
Sunil K Lal
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Systematic Approach ◽  
Genome Wide

scholarly journals Reassortment Network of Influenza A Virus

2021 ◽  
Author(s):  
Xingfei Gong ◽  
Mingda Hu ◽  
Wei Chen ◽  
Haoyi Yang ◽  
Boqian Wang ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Spanning Tree ◽  
Influenza A ◽  
Phylogenetic Trees ◽  
Minimum Spanning Tree ◽  
Genome Sequences ◽  
Genetic Characteristics ◽  
Time Period ◽  
Genome Wide ◽  
History Of

AbstractInfluenza A virus (IAV) genomes are composed of eight single-stranded RNA segments. Genetic exchange through reassortment of the segmented genomes often endows IAVs with new genetic characteristics, which may affect transmissibility and pathogenicity. However, a comprehensive understood of the reassortment history of IAVs remains poorly studied. To this end, we assembled 40296 whole-genome sequences of IAVs for analysis. Using a new clustering method based on Mean Pairwise Distances in the phylogenetic trees, we classified each segment of IAVs into clades. Correspondingly, reassortment events among IAVs were detected by checking the segment clade compositions of related genomes under specific environment factors and time period. We systematically identified 1927 possible reassortment events of IAVs and constructed their reassortment network. Interestingly, minimum spanning tree of the reassortment network reproved that swine act as an intermediate host in the reassortment history of IAVs between avian and human. Moreover, reassortment patterns among related subtypes constructed in this study are consistent with previous studies. Taken together, our genome-wide reassorment analysis of all the IAVs offers an overview of the leaping evolution of the virus and a comprehensive network representing the relationships of IAVs.

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