Molecular Mechanism of Action of the Influenza PA-X Host Shutoff Protein
流感 PA-X 宿主关闭蛋白的分子机制
基本信息
- 批准号:9913984
- 负责人:
- 金额:$ 39.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-05-25 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAntiviral AgentsAvian InfluenzaBacterial InfectionsBindingBiological AssayCell Culture TechniquesCellsCessation of lifeCharacteristicsChickensComplexDNA-Directed RNA PolymeraseDataDiseaseDisease OutbreaksDrug TargetingEpithelial CellsExonsFutureGene ExpressionGene SilencingGoalsImmuneImmune responseImmunomodulatorsInfectionInflammatory ResponseInflammatory Response PathwayInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A Virus, H5N1 SubtypeInfluenza A virusInnate Immune ResponseInterferon Type IInterferonsKnowledgeLabelLengthLinkLungMessenger RNAModelingMolecularMolecular Mechanisms of ActionMorbidity - disease rateMusOutcomePathogenicityPathway interactionsPharmaceutical PreparationsPlayPolymerasePositioning AttributeProcessProteinsPublic HealthRNARNA DegradationRNA Polymerase IIRNA ProcessingRNA SplicingRegulationReporterResearchRibonucleasesRoleSiteSpecificityTestingTranslationsVariantViralViral PneumoniaViral ProteinsVirusVirus DiseasesVirus ReplicationWorkanalysis pipelinebasebronchial epitheliumcellular targetingcytokinecytokine release syndromeexperienceexperimental studyhuman pathogenimmunoregulationimprovedin vivoinfluenzavirusinnovationknock-downlung injurymRNA Transcript Degradationmortalitymouse modelmutantnovelpandemic diseasepreventprotein functionresponsesecondary infectionsuccesstranscriptometranscriptome sequencingviral RNA
项目摘要
Project summary. The innate immune and inflammatory response to influenza A virus is a major contributor to
influenza disease, because it promotes viral pneumonia and secondary infections through lung damage. As a
consequence, it has recently become clear that blocking influenza virus replication is not sufficient to treat
influenza disease. New strategies to block the innate immune and inflammatory responses need to be
developed. These strategies could take advantage of the role of viral proteins in modulating host responses,
including the host shutoff factor PA-X, which targets host RNAs for degradation. PA-X inhibits immune
responses, and viruses that lack PA-X trigger stronger cytokine responses in mouse and chicken infection
models. However, these stronger responses do not promote clearance, but in many cases result in increased
morbidity and mortality. This indicates that PA-X has a different function from other influenza immune
modulators, and that PA-X can be protective for the host. Defining the mechanism of action of PA-X will be
important to understand the unique contribution of PA-X to virus-host interplay and to exploit it to modulate
host responses to influenza. While host shutoff factors are usually considered indiscriminate, we have found
that PA-X is selective, and targets specific types of RNAs. Particularly, we have uncovered a connection
between PA-X and splicing of host RNAs. We have found that PA-X preferentially degrades spliced RNAs in
infected cells and, through proximity-dependent protein labeling, we have identified candidate interaction
partners of PA-X, which are cellular proteins involved in RNA splicing and 3' end processing. These data have
led us to the central hypothesis of this project: PA-X selectively targets RNAs through interactions with cellular
splicing and RNA processing machinery. The connection between splicing and PA-X activity is novel among
host shutoff RNases. It also suggests that through interactions with splicing factors, PA-X may differentially
regulate host RNAs with important functions in immune and inflammatory responses, including spliced vs.
intronless types of interferons, key antiviral cytokines. Our objective is to examine the connection between
PA-X and cellular mRNA splicing and its effects on cytokine regulation. The long-term goal of our research is to
link the molecular function of PA-X to its role in vivo. In Aim 1, we will determine how the number of splice sites
and their position affects PA-X's ability to target RNAs, and how widely applicable this is to PA-X variants from
divergent influenza strains. We will use a combination of reporter assays and high-throughout RNAseq. In Aim
2, we will define the role of candidate cellular co-factors of PA-X in RNA targeting by PA-X, particularly
association with target RNAs and subcellular localization of PA-X using knock-down approaches. We will then
use viral mutants to test the role of these interactions in mouse infections. We expect that these experiments
will define RNA characteristics and proteins that are important for PA-X activity, expanding our understanding
of influenza-host interplay and pointing to strategies to alter PA-X activity for immune modulation.
项目总结。先天免疫和炎症反应是对甲型流感病毒的主要贡献者
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Marta Maria Gaglia其他文献
Marta Maria Gaglia的其他文献
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{{ truncateString('Marta Maria Gaglia', 18)}}的其他基金
Determining how Kaposi’s sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses
确定卡波西肉瘤相关疱疹病毒如何劫持半胱天冬酶功能以抑制抗病毒反应
- 批准号:
10729751 - 财政年份:2021
- 资助金额:
$ 39.42万 - 项目类别:
Determining how Kaposi's sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses
确定卡波西肉瘤相关疱疹病毒如何劫持半胱天冬酶功能以抑制抗病毒反应
- 批准号:
10403006 - 财政年份:2021
- 资助金额:
$ 39.42万 - 项目类别:
Molecular Mechanism of Action of the Influenza PA-X Host Shutoff Protein
流感 PA-X 宿主关闭蛋白的分子机制
- 批准号:
10381706 - 财政年份:2018
- 资助金额:
$ 39.42万 - 项目类别:
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