How Do Arboviruses Escape the Mosquito Midgut?- Analysis of a Novel Mechanism
How Do Arboviruses Escape the Mosquito Midgut?- Analysis of a Novel Mechanism
批准号:
10289718
负责人:
Alexander W E Franz
金额:
$38.27万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-11-03 至 2024-10-31
关键词:
ADAMTSAedesAffectApplications GrantsArbovirusesBasal laminaBiochemicalCRISPR/Cas technologyCathepsin LChikungunya virusCollagen Type IVCommunitiesComplexCulicidaeDataDengueDengue VirusDevelopmentDigestionEnzymesEpithelial CellsEukaryotaExclusionExtracellular MatrixGene ExpressionGenesGeneticGenetic MarkersHumanImaging technologyIn SituIndividualInfectionIngestionInterstitial CollagenaseIonsLamininMatrix MetalloproteinasesMayaro virusMetalloproteasesMethodologyMidgutModificationMolecularNatureOralOrganOrganismOutcomePeptide HydrolasesPeptidoglycanPhenotypePopulationPost-Translational Protein ProcessingProcessProteinsProteomicsRNA interference screenResearchResearch PersonnelResolutionSalineSalivary GlandsScanning Electron MicroscopySecondary toSerineStretchingStructureTestingThickTimeTissue Inhibitor of MetalloproteinasesTissuesTransgenic OrganismsVariantViralVirionVirusVirus DiseasesZIKAZika Virusbasechikungunyacollagenasedetection assayexperimental studyinterestknockout genemolecular markermonolayermosquito-bornenovelnovel strategiesnovel virusoverexpressionpolyclonal antibodyproteinase Inthree dimensional structuretooltranscriptome sequencingvectorvector competencevector mosquitoviral transmission
中文摘要
标题:
英文摘要
Title:
How do arboviruses escape the mosquito midgut? - Analysis of a novel mechanism
Project Summary. Following ingestion of a viremic bloodmeal from a vertebrate host, an
arbovirus enters the midgut lumen of a mosquito vector (such as Aedes aegypti) along with the
bloodmeal. The virus then needs to enter and infect the midgut epithelial cells of the midgut
before the virus disseminates from the midgut to secondary tissues including the salivary
glands. Once these are infected, the mosquito transmits the virus to another vertebrate host
during probing. The molecular nature of the exit mechanism of the virus from the midgut, has
been unresolved so far. In this grant application, we will reveal this mechanism and its genetic
background using a multifaceted portfolio of state-of-the-art methodologies. Our previous
studies demonstrated that during bloodmeal digestion, chikungunya virus (CHIKV) exits the
mosquito midgut via the basal lamina (BL) surrounding the organ. The BL predominantly
consists of collagen IV and laminin and its typical pore size exclusion limit appears to be too
small for virions to pass through. However, during bloodmeal digestion, the BL alters its
structure as midgut-associated collagen IV becomes greatly diminished. We hypothesized that it
is this structural change in the BL that allows virions to exit the midgut during bloodmeal
digestion. In eukaryotes, known proteinases that modify the extracellular matrix including the BL
are matrix metalloproteinases, ADAM/ADAMTS, and serine collagenases. We hypothesize that
these classes of proteinases, which are also present in mosquitoes, are responsible for midgut
BL modification during bloodmeal digestion. To test these two hypotheses, we propose the
following three Specific Aims for this application: 1.) Analyze BL degradation/remodeling and
CHIKV dissemination in Ae. aegypti by ultrastructural studies and proteomic analysis; 2.)
Identify proteinases that are involved in the BL modification process during bloodmeal digestion
and CHIKV dissemination; 3.) Assess whether other viruses (such as Zika, dengue, and Mayaro
viruses) utilize the same midgut escape mechanism as observed for CHIKV and how transgenic
manipulation of proteinase-of-interest expression affects viral midgut escape in mosquitoes.
Completion of these Specific Aims will provide a comprehensive picture explaining the
mechanism of the midgut escape barrier, which key enzymes are involved in the mechanism,
and whether the mechanism elucidated for CHIKV is the paradigm for other arboviruses. Our
results will be critical for developing novel control strategies aimed at manipulating arbovirus
midgut escape in mosquitoes. Our findings will also provide the research community with the
possibility to develop novel genetic markers for vector competence based on midgut escape.
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DOI:
10.1371/journal.pntd.0010003
发表时间:
2021-11
期刊:
PLoS neglected tropical diseases
影响因子:
3.8
作者:
[Herd CS, Grant DG, Lin J, Franz AWE]
通讯作者:
Franz AWE
DOI:
10.1186/s12864-022-08327-9
发表时间:
2022-02-10
期刊:
BMC genomics
影响因子:
4.4
作者:
[Cui Y, Behura SK, Franz AWE]
通讯作者:
Franz AWE
Identification of the extracellular metallo-endopeptidases ADAM and ADAMTS in the yellow fever mosquito Aedes aegypti.
黄热病蚊子埃及伊蚊细胞外金属内肽酶 ADAM 和 ADAMTS 的鉴定。
DOI:
10.1016/j.ibmb.2022.103815
发表时间:
2022
期刊:
Insect biochemistry and molecular biology
影响因子:
3.8
作者:
[Herd,ChristieS, Yu,Xiudao, Cui,Yingjun, Franz,AlexanderWE]
通讯作者:
Franz,AlexanderWE
DOI:
10.3390/insects14070601
发表时间:
2023-07-03
期刊:
Insects
影响因子:
3
作者:
[]
通讯作者:
Heterogeneity of midgut cells and their differential responses to blood meal ingestion by the mosquito, Aedes aegypti.
中肠细胞的异质性及其对蚊子艾德斯埃及摄入血餐的差异反应。
DOI:
10.1016/j.ibmb.2020.103496
发表时间:
2020-12
期刊:
Insect biochemistry and molecular biology
影响因子:
3.8
作者:
[Cui Y, Franz AWE]
通讯作者:
Franz AWE
Optimization of low-threshold Cas9-based gene drive systems to introduce Zika virus resistance in Aedes aegypti
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批准号:10667935
-
项目类别:
-
资助金额:$53.7万
-
财政年份:2022
-
负责人:Alexander W E Franz
-
依托单位:
How Do Arboviruses Escape the Mosquito Midgut?- Analysis of a Novel Mechanism
-
批准号:10053287
-
项目类别:
-
资助金额:$38.28万
-
财政年份:2017
-
负责人:Alexander W E Franz
-
依托单位:
Transgenic Resistance of Aedes aegypti to the Four Serotypes of Dengue Virus
-
批准号:8748903
-
项目类别:
-
资助金额:$19.19万
-
财政年份:2014
-
负责人:Alexander W E Franz
-
依托单位:
Arbovirus midgut escape mechanisms
-
批准号:8777084
-
项目类别:
-
资助金额:$65.85万
-
财政年份:2011
-
负责人:Alexander W E Franz
-
依托单位:
RNAi as a modulator of arbovirus vector competence in transgenic Aedes aegypti
-
批准号:7241190
-
项目类别:
-
资助金额:$29.4万
-
财政年份:2007
-
负责人:Alexander W E Franz
-
依托单位:
RNAi as a modulator of arbovirus vector competence in transgenic Aedes aegypti
-
批准号:7910719
-
项目类别:
-
资助金额:$28.55万
-
财政年份:2007
-
负责人:Alexander W E Franz
-
依托单位:
RNAi as a modulator of arbovirus vector competence in transgenic Aedes aegypti
-
批准号:7662309
-
项目类别:
-
资助金额:$28.84万
-
财政年份:2007
-
负责人:Alexander W E Franz
-
依托单位:
RNAi as a modulator of arbovirus vector competence in transgenic Aedes aegypti
-
批准号:7499727
-
项目类别:
-
资助金额:$28.84万
-
财政年份:2007
-
负责人:Alexander W E Franz
-
依托单位:
海外基金