Coxsackie Myocarditis and Viral Persistence in the Heart
Coxsackie Myocarditis and Viral Persistence in the Heart
批准号:
7160517
负责人:
J. Lindsay Whitton
金额:
$44.49万
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-01-01 至 2008-11-30
关键词:
5&apos Untranslated RegionsAblationAdultAffectAgeAntigen PresentationAntiviral AgentsB-LymphocytesCD55 AntigensCD8B1 geneCVBR45Cell CycleCell ProliferationCell divisionCellsCentral Nervous System InfectionsComplementCoxsackie VirusesCultured CellsDiseaseEncephalitisEpitopesEquationFailureGene ExpressionGenomeHeartHourHumanHuman poliovirusImmune responseImmune systemImmunityImmunohistochemistryIn Situ HybridizationInfectionInflammationInternal Ribosome Entry SiteKineticsKnockout MiceLifeLinkMHC Class I GenesMapsMeningitisMusMutateMutationMyocardialMyocarditisMyocardiumNeonatalNeuraxisNumbersOrganPancreasPaperPathogenesisPathologyPathway interactionsPlayPoliovirusesPolyproteinsPredispositionPrincipal InvestigatorProductionProliferatingProteinsPublishingRNARecombinantsReporter GenesReportingResearch PersonnelResponse ElementsRoleSeveritiesSideStructure of germinal center of lymph nodeT-LymphocyteT-Lymphocyte EpitopesTestingTherapeutic InterventionThinkingTimeTissuesTransgenic OrganismsTropismUntranslated RegionsVaccinationViralVirusVirus DiseasesVirus Receptorsadenovirus receptorcell typecytokinedesignheart cellimmunopathologyimprovedin vivoinfected B cellinjuredmutantneonatenovel strategiespathogenperforinpreventprogramsreceptorreceptor bindingreceptor expressionresponsetissue culturetissue/cell culture
中文摘要
柯萨奇病毒(CVB)是人类重要的病原体,可引起心肌炎、脑膜炎等
可能致命的疾病,尤其是在新生儿中。这项建议针对CVB提出了五个具体目标
致病(目标1-3)和免疫(目标4、5)。
目的1.柯萨奇柯萨奇病毒是否在体内优先感染增殖细胞?我们已经证明,在组织培养中,
细胞周期对CVB基因的表达和病毒的产生有重要影响。这在活体内也是如此吗,在
心脏、中枢神经系统还是免疫系统?我们将鉴定这些组织中的增殖细胞,
并将确定他们是否更容易受到感染。如果心脏在活体内受到损伤,这是否会改变其
对随后的CVB感染的易感性?
目标2.病毒的哪种成分对宿主细胞周期作出反应?接下来,我们将研究病毒的一面
方程式。我们假设内部核糖体进入部位可能是病毒的“反应元件”;这
将在组织培养和体内进行评估。
目的3.CVB受体在心脏和中枢神经系统的趋向性和发病机制中起什么作用?我们
应评估受体的表达水平。它们会随着年龄的增长而变化吗?继感染/组织
损伤,邻近细胞中的受体上调了吗?
目的4.CD8?T细胞对控制CVB感染有何作用?我们已经证明了,在CVB期间
感染后,CD8?T细胞可以降低病毒滴度,而且这种作用不需要穿孔素。什么效应器
功能是否参与了抗病毒的作用?这些效应器功能是否会导致组织损伤?
目的5.CVB如何有效地避免诱导强烈的CD8T细胞反应?大多数病毒感染
诱导高水平的抗病毒CD8+rl“细胞。CVB如何避免这种情况?我们能纠正这种情况吗?
英文摘要
Coxsackieviruses (CVB) are important human pathogens, causing myocarditis, meningitis, and other
diseases which may be lethal, especially in neonates. This proposal has five specific aims focused on CVB
pathogenesis (Aims 1-3) and immunity (Aims 4, 5).
Aim 1. Does CVB preferentially infect proliferating cells in vivo? We have shown, in tissue culture, that the
cell cycle exerts a dramatic effect on CVB gene expression & virus production. Is this also true in vivo, in
the heart, central nervous system, or immune system? We shall identify proliferating cells in these tissues,
and will determine if they are more susceptible to infection. If the heart is injured in vivo, does this alter its
susceptibility to subsequent CVB infection?
Aim 2. What component of the virus responds to the host cell cycle? Next, we shall study the viral side of
the equation. We hypothesize that the internal ribosome entry site may be the viral "response element"; this
will be evaluated in tissue culture, and in vivo.
Aim 3. What role do the proposed CVB receptors play in tropism & pathogenesis in the heart & CNS? We
shall evaluate the expression levels of the receptors. Do they change with age? Following infection / tissue
damage, are the receptors upregulated in neighboring cells?
Aim 4. How do CD8 ¿ T cells contribute to the control of CVB infection ? We have shown that, during CVB
infection, CD8 ¿ T cells can reduce viral titers, and that this effect does not require perforin. What effector
functions are involved in the antiviral effect? Do these effector functions contribute to tissue damage?
Aim 5. How does CVB so effectively avoid inducing strong CD8 ¿ T cell responses? Most virus infections
induce high levels of antiviral CD8 + rl"cells. How does CVB avoid this? Can we rectify the situation?
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批准号:8524204
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资助金额:$47.38万
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依托单位:
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批准号:8258340
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资助金额:$47.0万
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海外基金