Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects
评估 SARS-CoV-2 感染人类受试者持久保护性免疫力的决定因素
基本信息
- 批准号:10265628
- 负责人:
- 金额:$ 71.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-06 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAfricaAntibodiesAreaAttenuatedB-LymphocytesBloodBlood CirculationCapsid ProteinsCellsChemicalsClinicalClinical TrialsCommunicable DiseasesCountryCuesDataDevelopmentDiseaseEffector CellFutureGenerationsGoalsHumanImmuneImmune responseImmune systemImmunityImmunizationImmunologic MemoryImmunologyIndividualInfectionInflammatory ResponseInnate Immune ResponseInnate Immune SystemLeadLymphocyteMaintenanceMalariaMalaria VaccinesMeasuresMediatingMemoryModelingMusOrganOutcomeParasitesParasitologyPlasmodiumPlasmodium falciparumPopulationPreventionProcessResearchResidenciesSamplingSentinelSporozoite vaccineSporozoitesSterilitySubunit VaccinesSurfaceSystemT-LymphocyteTechniquesTestingTimeTissuesVaccinationVaccine DesignVaccinesadaptive immune responsebasecircumsporozoite proteinclinically relevantexperienceinsightmalaria infectionmouse modelnovelprogramsresearch clinical testingresponsetoolvaccination strategyvaccine candidatevaccine developmentvaccine efficacyvaccine trialvaccinology
项目摘要
PROJECT SUMMARY
Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has already resulted in nearly 3
million laboratory diagnosed infections and over 200,000 deaths worldwide. There is no known pre-existing
immunity to SARS-CoV-2 in humans or licensed therapeutics to combat or limit infection. In the absence of
these pharmacological interventions, governments around the world have implemented stringent measures to
that curb the spread of SARS-CoV-2 to populations at risk of serious complications from infection. Efforts to
identify efficacious therapies and develop vaccines to counter infection and disease require time and ultimately
need to be guided by deep knowledge about this novel pathogen. Immune-directed therapies in particular
require a detailed understanding of the immune responses generated not only in severe COVID-19 disease but
also in the vast majority of individuals who develop non-severe disease. Innate immunity serves as the frontline
response to counter the early stages of infection and but is also critical for regulating the ensuing adaptive
immune response. In humans, anti-SARS-CoV-2 humoral immunity has gained significant attention while roles
for innate immunity and memory T cell responses have not been extensively studied. However, knowledge
gained from SARS-CoV-1 studies indicate that T cell immunity is critical in virus control. In these SARS-CoV-1
infected mice, the induction of the innate type I Interferon signaling cascade is delayed. Yet mice lacking this
innate immune response exhibited greater numbers of virus specific T cells in their lungs. Thus, this
dysregulated innate immune response impairs anti-SARS-CoV-1 T cell memory. Whether SARS-CoV-2
infection induces protective memory T cells and if the durability of anti-SARS-CoV-2 T cell memory is
influenced by innate immunity are all currently unexplored. In humans, the innate immune response induced in
non-severe COVID-19 disease is not well characterized. However, preliminary studies in cultured cells and
animal models indicate that upon SARS-CoV-2 infection, there is a restricted and delayed induction of innate
immunity resulting in limited induction of cytokines and chemokines critical for immune cell recruitment. We
predict that the vast majority of COVID-19 infected individuals will exhibit a dysregulated innate immune
response typified by delayed and limited inflammatory signaling. If true, such a compromised innate immune
response could in turn induce limited short-lived adaptive immunity. Indeed, studies from SARS-CoV-1
infections indicate that humoral responses are short-lived in recovered patients. To our knowledge, no studies
have examined memory durability in COVID-19 subjects. In this proposal, we will interrogate samples from a
prospective longitudinal cohort of Seattle residents to examine if aberrant T cell memory is induced during
SARS-CoV-2 infection and importantly if this impaired memory stems from dysregulated innate immunity.
Furthermore, mechanistic studies in the hACE2 transgenic mouse model, where SARS-CoV-2 infection results
in mild disease, will identify how innate immunity shapes anti-SARS CoV-2 T cell responses.
项目总结
由SARS-CoV-2病毒引发的2019年冠状病毒病(新冠肺炎)已造成近3
全球有100万人被实验室诊断为感染,20多万人死亡。没有已知的预先存在的
人类对SARS-CoV-2的免疫力或获得许可的治疗方法以对抗或限制感染。在没有的情况下
在这些药物干预下,世界各国政府都采取了严格的措施来
这抑制了SARS-CoV-2病毒向感染严重并发症风险人群的传播。努力实现
确定有效的治疗方法和开发疫苗来对抗感染和疾病需要时间和最终
需要以对这种新病原体的深入了解为指导。特别是免疫导向疗法
需要详细了解不仅在严重的新冠肺炎病中产生的免疫反应,而且
在发展为非严重疾病的绝大多数人中也是如此。先天免疫作为前线
反应以对抗感染的早期阶段,但也是调节随后的适应性的关键
免疫反应。在人类中,抗SARS-CoV-2体液免疫在发挥作用的同时,也受到了极大的关注
对于先天免疫和记忆,T细胞反应还没有得到广泛的研究。然而,知识
SARS-CoV-1研究表明,T细胞免疫在病毒控制中至关重要。在这些SARS-CoV-1中
感染小鼠后,先天I型干扰素信号级联的诱导被延迟。然而,缺乏这一点的老鼠
先天免疫反应在他们的肺中表现出更多的病毒特异性T细胞。因此,这一点
调节失调的先天免疫反应损害抗SARS-CoV-1 T细胞记忆。SARS-CoV-2是否
感染诱导保护性记忆T细胞,如果抗SARS-CoV-2 T细胞记忆的持久性
受先天免疫的影响,目前都是未知的。在人类中,诱导的先天免疫反应
非重症新冠肺炎病的特点不好。然而,在培养细胞和
动物模型表明,在SARS-CoV-2感染后,先天的诱导受到限制和延迟。
免疫导致对免疫细胞募集至关重要的细胞因子和趋化因子的有限诱导。我们
预测绝大多数新冠肺炎感染者将表现出调节失调的先天免疫
以延迟和有限的炎症信号为典型的反应。如果是真的,这种受损的先天免疫力
反应反过来又能诱导有限的短暂适应性免疫。事实上,对SARS-CoV-1的研究
感染表明,康复患者的体液反应是短暂的。据我们所知,没有研究
研究了新冠肺炎受试者的记忆耐久性。在这份提案中,我们将询问来自
对西雅图居民进行前瞻性纵向队列研究,以检查在
SARS-CoV-2感染,更重要的是,如果这种记忆受损源于调节失调的先天免疫。
此外,在hACE2转基因小鼠模型中,SARS-CoV-2感染导致的机制研究
在轻度疾病中,将确定先天免疫如何塑造抗SARS CoV-2 T细胞反应。
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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Stefan HI Kappe其他文献
Stefan HI Kappe的其他文献
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{{ truncateString('Stefan HI Kappe', 18)}}的其他基金
Parasite and host cell factors involved in the formation and persistence of Plasmodium vivax hypnozoites
寄生虫和宿主细胞因子参与间日疟原虫休眠子的形成和持续存在
- 批准号:
10564073 - 财政年份:2023
- 资助金额:
$ 71.28万 - 项目类别:
Biologically informed design of CD8+ T cell-dependent pre-erythrocytic stage malaria vaccines
CD8 T 细胞依赖性红细胞前阶段疟疾疫苗的生物学知情设计
- 批准号:
10341058 - 财政年份:2021
- 资助金额:
$ 71.28万 - 项目类别:
Biologically informed design of CD8+ T cell-dependent pre-erythrocytic stage malaria vaccines
CD8 T 细胞依赖性红细胞前阶段疟疾疫苗的生物学知情设计
- 批准号:
10558591 - 财政年份:2021
- 资助金额:
$ 71.28万 - 项目类别:
Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects
评估 SARS-CoV-2 感染人类受试者持久保护性免疫力的决定因素
- 批准号:
10375774 - 财政年份:2019
- 资助金额:
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Inducing durable, protective immune memory against malaria
诱导针对疟疾的持久、保护性免疫记忆
- 批准号:
10084807 - 财政年份:2019
- 资助金额:
$ 71.28万 - 项目类别:
Inducing durable, protective immune memory against malaria
诱导针对疟疾的持久、保护性免疫记忆
- 批准号:
10545746 - 财政年份:2019
- 资助金额:
$ 71.28万 - 项目类别:
Molecular Determinants of Sporozoite / Host Cell Interactions
子孢子/宿主细胞相互作用的分子决定因素
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10192640 - 财政年份:2018
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Refining Mendelian genetics of malaria parasites
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10216647 - 财政年份:2017
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