Viral and host factors in neuroinvasion of encephalitis alphaviruses
脑炎甲病毒神经侵袭的病毒和宿主因素
基本信息
- 批准号:10389982
- 负责人:
- 金额:$ 63.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-05 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAlphavirusAlphavirus InfectionsAreaAstrocytesBindingBinding SitesBiological WarfareBioterrorismBlood - brain barrier anatomyBrainBrain imagingCategory B pathogenCaveolinsCellsCessation of lifeDendritic CellsDiseaseDisease OutbreaksEncephalitisExhibitsFutureHematogenousHematopoieticHeparitin SulfateHeterogeneityHumanHuman ActivitiesIFNAR1 geneImaging TechniquesImmuneImmunoelectron MicroscopyIn VitroIncidenceInfectionInjuryInnate Immune ResponseIntegration Host FactorsInterferon Type IInterferonsIntranasal AdministrationInvadedLatin AmericaLymphoid TissueMapsMediatingMicroRNAsMicrogliaModelingMyeloid CellsNeuraxisNeuronsNew EnglandPericytesPeripheralPhenotypePublishingRegistriesRoleRouteSentinelSerumSignal TransductionSiteSouth AmericaTestingTherapeuticTropismUnited StatesUnited States National Institutes of HealthVenezuelanVenezuelan Equine Encephalitis VirusViralViral VectorVirulenceVirulence FactorsVirusVirus ReplicationWestern Equine Encephalitis Virusadaptive immune responseblood-brain barrier disruptionbrain cellbrain endothelial cellcell typeclimate changecytokineexperimental studygenomic locusgulf coasthuman modelin vivomacrophagemembermortalitymouse modelmutantnanoluciferaseneurotropic virusneurovascular unitnovelpathogenpreventreceptorresponsesubcutaneoustraffickingtranscytosisvector mosquitovector-borne
项目摘要
SUMMARY
The long-term objective of this multi-PI project is to determine how host-pathogen interactions
impact entry, infection, and spread of encephalitic alphaviruses in the central nervous system
(CNS). The vector-borne neurotropic viruses, Venezuelan, eastern, and western equine
encephalitis viruses (VEEV, EEEV, WEEV), invade the CNS after subcutaneous inoculation and
initial interaction with immune sentinel cells, such as macrophages and dendritic cells (DCs)
(VEEV), or fibroblastic, osteoblastic and other cell types (EEEV, WEEV). Both EEEV and VEEV
enter the brain via the hematogenous route but only VEEV is found in olfactory neurons. The
CNS lacks intraparenchymal lymphoid tissues and cannot initiate adaptive immune responses;
thus, it mainly relies on innate responses communicated through local and systemic cytokine
secretion, which modulate the status of resident neural cells and limits viral neuroinvasion and
the extent of infection. CNSresident cells may include multiple members of the neurovascular
unit (NVU) such as brain microvascular endothelial cells (BMECs), pericytes, astrocytes,
microglia and neurons themselves that may be infected directly or acted upon by regionally or
systemically produced cytokines. VEEV is a highly lymphotropic virus eliciting robust serum
cytokine responses after peripheral inoculation, while EEEV tropism in lymphoid tissues is
highly restricted, and serum cytokine responses are much lower, and in the case of type I IFN,
often undetectable. In published studies, two primary virulence factors for EEEV in human and
murine models defined mechanisms that suppresses replication in immune sentinel myeloid
cells and greatly limit innate immune (especially interferon) responses to EEEV infection in vitro
and in vivo1. How these factors, which include the presence of binding sites for the
hematopoietic cell-specific microRNA, mir142-3p, in the EEEV 3' untranslated region (UTR)1-3,
and efficient binding of EEEV to heparan sulfate (HS) receptors on cells4,5, impact the
differential neuroinvasion and CNS dissemination of EEEV versus VEEV is unknown.
Supporting the idea that differences in EEEV versus VEEV cytokine induction may be critical to
neuroinvasion, we found that type I IFN-dependent responses directly regulate transcytosis,
preventing alphavirus entry across the BBB and modulating the level of infection and injury in
cells of the NVU6. Thus, systemic and local cytokine responses during alphavirus infection
induce BMECs and pericytes to regulate viral entry at the blood-brain barrier (BBB) and
potentially other CNS sites. This is consistent with the relative extent of virus replication at
terminal stages of disease as EEEV exhibits widespread infection of neurons throughout the
CNS while VEEV replication is much more focal (unpublished). Using mutant VEEV and EEEV,
novel viral vectors that express indicators of infection (e.g., eGFP, nanoLuciferase) in vivo, we
have observed regional heterogeneity in dominant sites of entry between these alphaviruses.
With regard to BBB entry, our studies also indicate that viral neuroinvasion precedes BBB
disruption, utilizing caveolin-mediated transcytosis to cross the BBB. We hypothesize that type
I interferon responses differentially impact the entry and infection of EEEV and VEEV at
the NVU via virus-specific induction of replication-restricting innate immune responses.
To test these hypotheses we will:
Aim 1. Define alphavirus and host specific mechanism in vitro that regulate viral entry
and infection at the NVU.
Aim 2: Define the in vivo functional role of type I IFN in protection from alphavirus
neuroinvasion at the NVU.
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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WILLIAM B KLIMSTRA其他文献
WILLIAM B KLIMSTRA的其他文献
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{{ truncateString('WILLIAM B KLIMSTRA', 18)}}的其他基金
Viral and host factors in neuroinvasion of encephalitis alphaviruses
脑炎甲病毒神经侵袭的病毒和宿主因素
- 批准号:
10659110 - 财政年份:2022
- 资助金额:
$ 63.49万 - 项目类别:
An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses
针对脑炎甲病毒的减毒活疫苗的知情方法
- 批准号:
10027464 - 财政年份:2020
- 资助金额:
$ 63.49万 - 项目类别:
An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses
针对脑炎甲病毒的减毒活疫苗的知情方法
- 批准号:
10405637 - 财政年份:2020
- 资助金额:
$ 63.49万 - 项目类别:
An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses
针对脑炎甲病毒的减毒活疫苗的知情方法
- 批准号:
10188419 - 财政年份:2020
- 资助金额:
$ 63.49万 - 项目类别:
An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses
针对脑炎甲病毒的减毒活疫苗的知情方法
- 批准号:
10674134 - 财政年份:2020
- 资助金额:
$ 63.49万 - 项目类别:
An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses
针对脑炎甲病毒的减毒活疫苗的知情方法
- 批准号:
10636632 - 财政年份:2020
- 资助金额:
$ 63.49万 - 项目类别:
Development of a novel live attenuated vaccine for eastern equine encephalitis virus
新型东部马脑炎病毒减毒活疫苗的研制
- 批准号:
8869837 - 财政年份:2015
- 资助金额:
$ 63.49万 - 项目类别:
Characterization of microRNA binding sites in the eastern equine encephalitis virus 3'NTR
东部马脑炎病毒 3NTR 中 microRNA 结合位点的表征
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8966629 - 财政年份:2014
- 资助金额:
$ 63.49万 - 项目类别:
Characterization of microRNA binding sites in the eastern equine encephalitis virus 3'NTR
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8821225 - 财政年份:2014
- 资助金额:
$ 63.49万 - 项目类别:
Molecular mechanisms of eastern equine encephalitis virus pathogenesis
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- 批准号:
9594677 - 财政年份:2012
- 资助金额:
$ 63.49万 - 项目类别:
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