Vagal airway sensory nerve activation by beta-coronavirus spike protein
Vagal airway sensory nerve activation by beta-coronavirus spike protein
批准号:
10748485
负责人:
Joyce Sooyeon Kim
金额:
$6.95万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-01 至 2025-08-31
关键词:
2019-nCoVACE2Action PotentialsAddressAffinityAlveolusAngiotensin ReceptorAsthmaBindingBronchiBronchoconstrictionC FiberCOVID-19 pandemicCell membraneCellsChildChronicChronic Obstructive Pulmonary DiseaseCommon ColdCommunitiesCoronavirusCoronavirus spike proteinCoughingDataDiseaseElectrophysiology (science)EmbryoEpithelial CellsFellowshipFunctional disorderGoalsImaging TechniquesIndividualInfectionIon ChannelLeadLungMediatingMediatorMembraneMembrane GlycoproteinsMiddle East Respiratory Syndrome CoronavirusMolecularMusNerveNervous SystemNeural CrestNeuronsNociceptionNociceptorsNodose GanglionNoseOropharyngealPhenotypeProcessProductionProtein SubunitsProteinsReflex actionResearch ProposalsRespiratory DiseaseRespiratory MucosaRespiratory SystemRespiratory Tract InfectionsReverse Transcriptase Polymerase Chain ReactionSARS coronavirusSARS-CoV-2 spike proteinSecondary toSensorySneezingSore ThroatSpinalSpinal GangliaStimulusSurfaceSymptomsTLR4 geneTRPA channelTRPV1 geneToll-like receptorsTracheaVertebral columnViralVirusVirus Diseasesactivated Protein Cafferent nerveasthma exacerbationbetacoronavirusextracellularhuman diseaseinsightmRNA Expressionnovelpatch clampreceptorrespiratoryrespiratory virustheoriestransmission processtwo-photonvirtualvirus morphology
中文摘要
项目总结
感觉神经,特别是伤害性C纤维的激活,是大多数呼吸系统疾病的一个特征
病毒。这种激活的证据可以在C纤维激活的经典结果中找到
包括打喷嚏、喉咙痛、咳嗽和反射性分泌物。同时也造成了麻烦
病毒感染的症状,这些神经的激活允许病毒逃离身体并被
传播给其他宿主,即伤害性感受器的激活会放大病毒在社区中的传播。此外,
呼吸道迷走神经C纤维的激活可导致强反射性支气管收缩和过度
可能导致哮喘加重的分泌物,特别是在儿童中。给定
与人类疾病的相关性,令人惊讶的是,人们对病毒感染如何诱导C纤维知之甚少
激活和敏化。在理论上,病毒感染通过两种一般方式导致C纤维激活
机械装置。第一种是病毒感染上皮细胞产生一种介体(S)
这刺激了C-纤维终末。第二,病毒本身直接激活神经。
第二种机制可能取决于特定的病毒类型。这项提案的重点是
第二种(直接)激活机制,因为它与冠状病毒有关。我猜想
冠状病毒刺突蛋白直接与C纤维末端相互作用,激活和
使伤害性C纤维敏化。我的初步数据,使用了三种正交法,支持
该结论认为,Spike蛋白直接激活(诱发动作电位放电)约40-
小鼠呼吸道有50%的迷走神经C纤维。我的第一个目标是描述迷走神经C纤维的亚型
也是为了评估SPEKE蛋白是否缺乏明显的
激活,导致C-纤维终末的敏化,即使它们对其他
激活刺激。我的第二个目标集中在机制上。我假设这种相互作用
涉及Spike蛋白中的Galactin-3倍,并且独立于Spike蛋白发生
受体ACE2或Toll样受体。不管近端的结合靶点是什么,我都会谈到我们的
假设激活是次要于TRPV1和/或TRPA1通道的开放的。这些目标
将使用单细胞RT-PCR分析呼吸道特异的mRNA表达
伤害性C纤维、细胞外和膜片钳电生理学和双光子实时成像
技巧。这些研究的结果有望为研究一种新的机制提供见解
冠状病毒诱导气道C纤维活化。
英文摘要
PROJECT SUMMARY
Activation of sensory nerves, in particular nociceptive C-fibers, is a feature of most respiratory
viruses. Evidence of such activation is found in the classical consequences of C-fiber activation
including sneezing, sore throat, coughing, and reflex secretions. As well as causing the troubling
symptoms of viral infection, the activation of these nerves allows viruses to escape the body and be
transmitted to other hosts, i.e. nociceptor activation amplifies viral spread in a community. In addition,
activation of airway vagal C-fibers can lead to strong reflex bronchoconstriction and excessive
secretions that likely contribute to the exacerbation of asthma particularly in children. Given the
relevance to human disease, surprisingly little is known about how virus infection induces C-fiber
activation and sensitization. In theory, viral infection leads to C-fiber activation by two general
mechanisms. The first is that viral infection of epithelial cells leads to the production of a mediator(s)
that stimulates the C-fiber terminals. The second is that the virus itself directly activates the nerves.
This second mechanism will likely be dependent on the specific virus type. This proposal focuses on
this second (direct) mechanism of activation as it relates to coronaviruses. I hypothesize that the
coronavirus spike protein interacts directly with C-fiber terminals in a manner that activates and
sensitizes the nociceptive C-fibers. My preliminary data, using three orthogonal approaches, support
the conclusion that the spike protein directly activates (evokes action potential discharge) about 40-
50% of vagal C-fibers in mouse airways. My first aim is to characterize the subtype of vagal C-fibers
that are activated by spike protein and also to assess whether the spike protein, short of overt
activation, leads to the sensitization of C-fiber terminals, i.e. renders them more sensitive to other
activating stimuli. My second aim focuses on the mechanism. I hypothesize that this interaction
involves the galactin-3 fold in the spike protein, and occurs independently of the spike protein
receptor ACE2 or toll-like receptors. Irrespective of the proximal binding target, I will address our
hypothesis that activation is secondary to the opening of TRPV1 and or TRPA1 channels. These aims
will be addressed using single cell RT-PCR analysis of mRNA expression in airway specific
nociceptive C-fibers, extracellular and patch-clamp electrophysiology, and 2-photon live imaging
techniques. The results of the studies are expected to provide insights into a novel mechanism of
coronavirus induced airway C-fiber activation.
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