Identifying genetic barriers to animal virus replication in human cells: Insights into zoonosis
识别人类细胞中动物病毒复制的遗传障碍:深入了解人畜共患病
基本信息
- 批准号:10794558
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-04 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimalsArterivirusBiologicalBloodBlood CirculationCRISPR screenCellsClustered Regularly Interspaced Short Palindromic RepeatsComplementDataData AnalysesDiseaseDominant GenesEbola virusEcologyEpidemicFaceFamilyGenesGeneticGenomic approachGeographic DistributionGoalsHIV-1HealthHigh-Throughput Nucleotide SequencingHumanInfectionIntegration Host FactorsInterferonsInvestmentsKnock-outMacrophageMembrane GlycoproteinsMetagenomicsMiddle East Respiratory Syndrome CoronavirusMolecular EvolutionMonkeysMutationNatural ImmunityNatural SelectionsNatural experimentNatureOrthologous GenePathogenicityPhenotypePlayPredispositionPrimatesProcessProteinsPublic HealthRelative RisksResearch PersonnelRiskRoleSARS coronavirusSIVSeriesSevere Acute Respiratory SyndromeSpecies SpecificityTestingTrainingViralViral Load resultViral ProteinsVirusVirus DiseasesVirus ReplicationWorkWritingZoonosesantiviral immunitycDNA Librarycofactorcross-species transmissionfunctional genomicsgenome analysisgenome sequencinggenome-wideinsightinterestknock-downnovelpandemic diseasepreventprospectivereceptorreceptor bindingsuccesstooltranscription factortransmission processviral transmissionvirus host interaction
项目摘要
Project Summary
Many emerging zoonotic viruses (animal viruses that transmit to humans) are highly pathogenic, having the
potential to cause deadly epidemics or even global pandemics. The risks zoonotic viruses pose are highlighted
by the emergence of the SARS/MERS coronaviruses, Ebola virus, and HIV-1, all of which are related to animal
viruses that were unknown before they caused substantial cases of disease in humans. Given the risk animal
viruses pose to humans, many researchers have turned to viral discovery—using genome sequencing tools and
metagenomic analyses, researchers hope to identify novel animal viruses before they emerge in humans. While
such efforts will prove invaluable to our understanding animal virus ecology, I seek to expand this work by
experimentally evaluating the zoonotic risk an animal virus poses. The crux of this proposal is as follows.
Experimental assessment of animal virus replication in human cells is crucial to evaluate zoonotic risk. However,
an animal virus facing one block to replication in a human cell will have the same phenotype as an animal virus
facing twenty blocks: producing low or no titers on human cells. But there is a critical difference between these
two scenarios—an animal virus facing one block poses a greater zoonotic risk because it requires fewer adaptive
mutations to replicate in human cells. Here, I propose to develop and demonstrate an experimental pipeline that
will distinguish between animal viruses facing few blocks to replication in human cells from those with many.
Host genetics plays a critical role in the species specificity of viruses. Divergence in host proteins used
for virus entry (cellular receptors), replication (cellular cofactors), and antiviral immunity (restriction factors) can
serve as potent barriers to virus infection in a new host species. Using hypothesis-driven studies and high-
throughput genomic approaches, I will systematically characterize this host-virus interaction landscape for an
understudied family of primate viruses (simarteriviruses). In Aim 1, I will assess the compatibility of diverse
simarteriviruses with the human version of their cellular receptor, CD163. In Aim 2, I will employ a CRISPR
screen to identify host cofactors required for simarterivirus replication. Then, I will use evolutionary signatures of
positive natural selection to identify those host proteins likely to engage simarteriviruses in a species-specific
manner. In Aim 3, I will identify antiviral proteins that block simarterivirus replication. Using a series of gene
knockdowns and complementations, I will evaluate the genetic barriers to simarterivirus replication in human
cells (Aims 1-3). Taken together, these aims will establish an experimental framework to evaluate the zoonotic
risk of an understudied animal virus, and will provide me with new training in 1) performing and writing about
molecular evolution analyses, 2) developing high-throughput sequencing projects and data analysis, and 3)
functional genomics, defined as the execution and analysis of genome-scale screens for phenotypes of interest.
项目总结
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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{{ truncateString('Cody Jay Warren', 18)}}的其他基金
Identifying genetic barriers to animal virus replication in human cells: Insights into zoonosis
识别人类细胞中动物病毒复制的遗传障碍:深入了解人畜共患病
- 批准号:
10461714 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
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