Vaccine-Induced Mucosal T-Cell Immunity to Respiratory Viruses in Dirty Mice
疫苗诱导脏小鼠粘膜 T 细胞对呼吸道病毒的免疫
基本信息
- 批准号:10746925
- 负责人:
- 金额:$ 23.33万
- 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
- 起止时间:2023-08-14 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAdjuvantAgonistAnimal ModelAntibodiesAntigensBiomedical ResearchCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCOVID-19 vaccineCell CountCellsCessation of lifeCommunicable DiseasesCytoprotectionDataDevelopmentEpitheliumEpitopesExposure toFormulationGeneticGenetic TranscriptionGoalsGranzymeGrowthHemagglutininHumanImmune responseImmunityImmunologicsInbred MouseInbreedingInfectionInfluenzaInfluenza A virusIntranasal AdministrationInvestigationLearningLinkLipid ALungLymphoidMembrane ProteinsMemoryMicrobeMolecularMucous MembraneMusMutationNeuraminidaseNucleoproteinsProteinsPublic HealthResearchResolutionRespiratory SystemRespiratory Tract InfectionsSeasonsSeminalSiteSpleenStructure of parenchyma of lungSubunit VaccinesSurfaceT cell responseT-LymphocyteTLR4 geneTestingTimeTissue DifferentiationTissuesTranslatingVaccinatedVaccinationVaccine ResearchVaccinesVariantViralViral Respiratory Tract InfectionVirus DiseasesWorkantiviral immunityclinical practiceconditioningeffector T cellefficacy studyexperiencegerm free conditionhuman modelhuman pathogenimmune system functionimprovedinfluenza A virus nucleoproteininfluenza virus straininfluenza virus vaccineinfluenzavirusinnovationinsightinterestmicrobialmicrobial communitymicrobiome compositionmicrobiotamouse modelmucosal vaccinenanoemulsionnovelpandemic influenzapre-clinicalpreconditioningprotective efficacypulmonary functionrespiratory pathogenrespiratory virusresponsetissue resident memory T cellvaccine developmentvaccine efficacyvaccine formulation
项目摘要
Abstract: Respiratory infections have been among the top three leading causes of global deaths for decades. Their
importance is reinforced by the emergence of novel highly transmissible respiratory pathogens, as witnessed in the current
SARS-CoV-2 and past influenza pandemics. Current influenza and SARS-CoV-2 vaccines are focused on eliciting
antibodies to highly mutable viral surface proteins, and frequent vaccine reformulations are needed to match the antigenicity
of constantly evolving viral strains or variants that evade vaccine-elicited antibodies. Therefore, elicitation of lung tissue-
resident memory T cells (TRMs), which recognize epitopes that are conserved across viral variants is critical to elicit broad
anti-viral immunity. We have developed combination adjuvant-based subunit mucosal vaccine formulations that elicit
exceptionally strong and functionally diverse lung/airway CD8 and CD4 TRMs and provide effective and broad
protection against influenza A virus (IAV) and SARS-CoV-2 in specific-pathogen-free (SPF) mice. However, a central
question is whether vaccine efficacy studies in SPF mice are translatable to humans, who are exposed to diverse
microbial species. In recent years, Dirty mice (SPF mice cohoused with pet store mice), have been used to model human
immune responses. Significantly, TRM numbers are greatly increased in Dirty mice, but the underlying mechanisms are
unknown. We have exciting preliminary data that the lungs and spleen of Dirty mice have markedly elevated number of
Granzyme BHI/CD44HI CD8 T cells with transcriptional attributes (T-betLO/EOMESLO/TCF-1LO) reminiscent of precursor
TRMs, which are poised for a TRM cell fate. The overarching goal is to exploit the high resolution of our combination
adjuvant-based vaccine approach and the Dirty mouse model to elucidate the effects of diverse microbial exposure on the
development of pre-TRMs and their subsequent differentiation into TRMs that protect against respiratory viruses. Specific
Aim 1 will test the hypothesis that diverse microbial exposure influences the development and protective functions of lung
TRMs against IAV and SARS-CoV-2. Here, we will compare the development and transcriptional programming of lung TRMs
induced by two combination adjuvant vaccine formulations and protective immunity to IAV and SARS-CoV-2 in SPF and
Dirty mice. Specific Aim 2 will test the hypothesis that diverse microbial exposure promotes the conditioning of
circulating/lymphoid pre-TRMs, leading to enhanced differentiation of TRMs in lungs of vaccinated Dirty mice. Here, in Dirty
and SPF mice, we will incisively dissect whether diverse microbial exposure enhances the pre-conditioning of naïve CD8
or CD4 T cells prior to vaccination and/or antigen-activated effector T cells during vaccination, to a TRM cell fate.
Impact:. Proposed studies will leverage microbial exposure to improve the rigor of mouse models to predict human
immune response to vaccines, and provide mechanistic insights into the development of TRMs in the lung under conditions
of diverse microbial exposure. Hence, this exploratory ‘high pay off’ R21 application blends significance and innovation
to lay the conceptual framework for further mechanistic investigations that will pave the way for the development of a
biologically relevant and translatable pre-clinical animal model to learn how we can leverage microbiota to enhance vaccine-
induced T-cell immunity to IAV and SARS-CoV-2, which are human respiratory viruses of public health importance.
摘要:几十年来,呼吸道感染一直是全球死亡的三大主要原因之一。他们的
新的高度传染性呼吸道病原体的出现加强了重要性,正如本报告所证明的那样。
SARS-CoV-2和过去的流感大流行。目前的流感和SARS-CoV-2疫苗主要集中在诱导
需要针对高度可变的病毒表面蛋白的抗体和频繁的疫苗重新配制才能匹配抗原性
不断进化的病毒株或变异株逃避疫苗引发的抗体。因此,肺组织的激发-
驻留记忆T细胞(TRM)识别在病毒变种中保守的表位,对于引发广泛的
抗病毒免疫。我们已经开发了基于佐剂的亚单位粘膜疫苗的组合配方,可以诱导
异常强大且功能多样的肺/呼吸道CD8和CD4TRMS,并提供有效和广泛的
对无特定病原体(SPF)小鼠的甲型流感病毒(IAV)和SARS-CoV-2的保护作用。然而,一个中央
问题是SPF小鼠的疫苗效力研究是否可以移植到人类身上,人类暴露在不同的
微生物种类。近年来,脏鼠(SPF鼠与宠物店鼠共居)被用来模拟人类
免疫反应。值得注意的是,肮脏小鼠的TRM数量大大增加,但其潜在机制是
未知。我们有令人兴奋的初步数据表明,肮脏的小鼠的肺和脾的数量显著增加。
具有前体转录属性的颗粒酶BHI/CD44HI CD8 T细胞(T-betLO/EOMESLO/TCF-1LO)
TRM,它们正准备迎接TRM细胞的命运。首要目标是利用我们组合的高分辨率
佐剂疫苗方法和脏鼠模型阐明不同微生物暴露对
前TRM的发展及其随后分化为TRM,以保护呼吸道病毒。特定的
目标1将验证不同微生物暴露影响肺发育和保护功能的假设
针对IAV和SARS-CoV-2的TRMS。在这里,我们将比较肺TRMS的发育和转录编程
两种联合佐剂疫苗对SPF和SARS-CoV-2疫苗的诱导和保护性免疫
肮脏的老鼠。特定目标2将检验不同的微生物暴露促进条件反射的假设
循环/淋巴系前TRMS,导致接种Dirty小鼠肺内TRMS的分化增强。在这里,在肮脏的
和SPF小鼠,我们将深入剖析不同的微生物暴露是否增强了幼稚CD8的预适应
或接种前的CD4T细胞和/或接种期间的抗原激活的效应T细胞,以TRM细胞的命运。
影响:。拟议中的研究将利用微生物暴露来提高小鼠模型预测人类的精确度
对疫苗的免疫应答,并提供对在条件下肺内TRMS发展的机械性见解
暴露在不同的微生物中。因此,这种探索性的高回报R21应用程序融合了意义和创新
为进一步的机械性调查奠定概念框架,为制定
生物相关和可翻译的临床前动物模型,以了解我们如何利用微生物区系来增强疫苗-
诱导T细胞对IAV和SARS-CoV-2的免疫,这两种病毒是对公共卫生具有重要意义的人类呼吸道病毒。
项目成果
期刊论文数量(0)
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Marulasiddappa Suresh其他文献
Marulasiddappa Suresh的其他文献
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{{ truncateString('Marulasiddappa Suresh', 18)}}的其他基金
Regenerative Capacity of Anti-Viral Memory CD8 T cells
抗病毒记忆CD8 T细胞的再生能力
- 批准号:
9232971 - 财政年份:2016
- 资助金额:
$ 23.33万 - 项目类别:
Novel Combination Adjuvant for Eliciting Systemic and Mucosal CD8 T Cell Memory
用于激发全身和粘膜 CD8 T 细胞记忆的新型组合佐剂
- 批准号:
9228321 - 财政年份:2016
- 资助金额:
$ 23.33万 - 项目类别:
Programming of Protective CD8 T-Cell Memory by Live and Adjuvanted Subunit Vaccin
通过活疫苗和佐剂亚单位疫苗对保护性 CD8 T 细胞记忆进行编程
- 批准号:
8369197 - 财政年份:2012
- 资助金额:
$ 23.33万 - 项目类别:
Programming of Protective CD8 T-Cell Memory by Live and Adjuvanted Subunit Vaccin
通过活疫苗和佐剂亚单位疫苗对保护性 CD8 T 细胞记忆进行编程
- 批准号:
8517578 - 财政年份:2012
- 资助金额:
$ 23.33万 - 项目类别:
Direct Regulation of CD8 T Cells by Interferon gamma
干扰素 γ 对 CD8 T 细胞的直接调节
- 批准号:
8070835 - 财政年份:2010
- 资助金额:
$ 23.33万 - 项目类别:
Direct Regulation of CD8 T Cells by Interferon gamma
干扰素 γ 对 CD8 T 细胞的直接调节
- 批准号:
7878289 - 财政年份:2009
- 资助金额:
$ 23.33万 - 项目类别:
Comparative Biomedical Sciences Training Program
比较生物医学科学培训计划
- 批准号:
10199087 - 财政年份:2007
- 资助金额:
$ 23.33万 - 项目类别:
Comparative Biomedical Sciences Training Program
比较生物医学科学培训计划
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10698130 - 财政年份:2007
- 资助金额:
$ 23.33万 - 项目类别:
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10552190 - 财政年份:2007
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- 批准号:
7198242 - 财政年份:2007
- 资助金额:
$ 23.33万 - 项目类别:
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