Genome-wide CRISPR screen Identifies Host Dependency Factors for Influenza A Virus Infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE141171 | GEO | 2019/11/30
REPOSITORIES: GEO
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Project description:Competition and interplay between host and viral gene expression programs is a critical determinant of infection susceptibility and a potential target for anti-viral therapies. Viral infection is well documented to induce the expression of numerous host genes that are part of the innate immune response. Here we show that infection of human lung epithelial cells with Influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. While these splicing-regulated genes are not enriched for known regulators of viral infection, we find that many of these genes do modulate the infection and/or replication of IAV in an siRNA screen. Moreover, inhibition of the IAV-induced splicing pattern in several genes tested also reduces viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein we have previously implicated in the nuclear speckle-dependent splicing of the IAV M transcript. Notably, hnRNP K abundance at nuclear speckles is increased upon IAV infection. We propose that this change in subnuclear localization may alter the accessibility of hnRNP K for host transcripts, thereby leading to a program of host splicing changes that promote IAV replication.
2020-12-10 | GSE142499 | GEO
Project description:Influenza A viruses (IAV) induces drastic host shut-off during infection. We use RNA-seq and ribosome profiling to systematically look at host genes RNA and translation levels along IAV infection. We show that host shutoff is mainly achieved by reduction in cellular mRNAs levels and that the high translation levels of IAV transcripts are driven by their strong accumulation compared to host transcripts. Interestingly, our systematic analysis reveals that host transcripts are affected differently by IAV infection and the extent of cellular mRNAs reduction is strongly related to transcripts’ length and GC content.
2016-08-15 | GSE82232 | GEO
Project description:Influenza A Virus (IAV) is a recurring respiratory virus with antiviral therapies of limited use. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses with three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we mapped 332 IAV-human protein-protein interactions and identified 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza revealed several genes, including the structural scaffold protein AHNAK, with predicted loss-of-function variants that were also identified in our proteomic analyses. Of our identified host factors, 54 significantly altered IAV infection upon siRNA knockdown, and two factors, COPB1 and AHNAK, were also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppressed IAV replication, with three targeting ATP6V1A, CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT. This project includes the AP-MS data; all global proteomic data (abundance and phosphorylation) has been submitted separately as its own dataset and has its own dataset identifier.
2023-07-25 | PXD036077 | Pride
Project description:Influenza A Virus (IAV) is a recurring respiratory virus with antiviral therapies of limited use. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses with three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we mapped 332 IAV-human protein-protein interactions and identified 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza revealed several genes, including the structural scaffold protein AHNAK, with predicted loss-of-function variants that were also identified in our proteomic analyses. Of our identified host factors, 54 significantly altered IAV infection upon siRNA knockdown, and two factors, COPB1 and AHNAK, were also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppressed IAV replication, with three targeting ATP6V1A, CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT. This project includes the global proteomic data (abundance and phosphorylation), the AP-MS data has been submitted separately as its own dataset and has its own dataset identifier.
2023-07-25 | PXD035900 | Pride
Project description:Influenza A Virus (IAV) is a recurring respiratory virus with antiviral therapies of limited use. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry (AP-MS) and global phosphoproteomic and protein abundance analyses with three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we mapped 332 IAV-human protein-protein interactions (PPIs) and identified 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza revealed several genes, including the structural scaffold protein AHNAK, with predicted loss-of-function variants that were also identified in our proteomic analyses. Of our identified host factors, 54 significantly altered IAV infection upon siRNA knockdown, and two factors, COPB1 and AHNAK, were also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppressed IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT. This project includes endogenous IP data from A549 cells and NHBE cells infected with H5N1 IAV validating IAV-host PPIs M2-ATP6V1A and NEP-AHNAK, respectively. M2-ATP6V1A and NEP-AHNAK PPIs were first identified in AP-MS data that is submitted under its own dataset identifier (PXD036077).
2023-07-25 | PXD041663 | Pride
Project description:Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.
2024-08-08 | PXD052229 | Pride
Project description:Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.
2024-08-06 | GSE268254 | GEO
Project description:Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global health threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a complementing strategy for infection treatment through targeting host immune mechanisms. However, the limited understanding of the host factors and their regulatory mechanisms involved in host immune defense against infections has impeded HDT development. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) elicits host protective immunity against Mtb. Mechanistically, TRIM27 enters host cell nucleus upon Mtb infection to function as a transcription activator of transcription factor EB (TFEB). TRIM27 binds to TFEB promoter and the TFEB transcription factor cAMP responsive element binding protein 1 (CREB1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity towards TFEB, eventually leading to autophagy activation and pathogen clearance. Thus, TRIM27 contributes to host anti-Mtb immunity and targeting TRIM27/CREB1/TFEB axis serves as a promising HDT-based TB treatment.
2024-07-03 | GSE237039 | GEO
Project description:Background: The role of host encoded microRNAs in genetically determined host susceptibility to influenza A virus (IAV) infection has not been explored. We therefore compared changes in pulmonary miRNA expression during IAV infection in two inbred mouse strains with differential susceptibility to IAV infection. Results: miRNA expression profiles were determined in lungs of the more susceptible mouse strain DBA/2J and the less susceptible strain C57BL/6J within 120 hours post infection (hpi) with IAV (H1N1) PR8. Even the miRNomes of uninfected lungs differed substantially between the two strains. After a period of relative quiescence, major miRNome reprogramming was detected in both strains by 48 hpi and increased through 120 hpi. Distinct groups of miRNAs regulated by IAV infection could be defined: (1) miRNAs (n= 39) whose expression correlated with HA mRNA expression and represented the general response to IAV infection independent of host genetic background; (2) miRNAs (n=20) whose expression correlated with HA mRNA expression but differed between the two strains; and (3) remarkably, miRNAs (n=8) whose abundance even in uninfected lungs differentiated nearly perfectly (area under the ROC curve >0.99) between the two strains throughout the time course. Higher abundance of miRNAs with anti-apoptotic functions and lower abundance of miRNAs regulating the PI3K-Akt pathway were associated with the more susceptible DBA/2J strain. Conclusions: These results suggest that differences in host miRNA abundance before and during IAV infection are in part determined genetically and contribute to susceptibility to IAV infection in this experimental mouse model, and likely in humans.
2017-06-12 | GSE89064 | GEO
Project description:To characterize the host response to pandemic IAV infection in its natural target cells, we infected primary human airway epithelial cell (hAEC) cultures wild-type pandemic IAV (WT) or a NS1 mutant virus (NS1R38A) with abrogated dsRNA binding capacity at a multiplicity of infection (MOI) of 0.03. We then profiled the transcriptomes of uninfected cells as well as cells harvested 18 hours post-infection (hpi) using single-cell RNA sequencing (scRNA-seq).
2022-09-22 | E-MTAB-12159 | biostudies-arrayexpress