Immunoprotective Properties of Tissue-resident Memory T Cells in Mice and Humans within Mucosal Sites

小鼠和人类粘膜部位组织驻留记忆 T 细胞的免疫保护特性

• 批准号: 10642271
• 负责人: Jennifer M Lund
• 金额: $ 3.13万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10642271
• 关键词: Address; Animal Model; Antigens; Apoptosis; Architecture; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Density; Cell physiology; Cells; Characteristics; Clinical; Communicable Diseases; Containment; Cues; Data; Disease; Drug or chemical Tissue Distribution; Event; Exposure to; Future; Gene Expression Profile; Gene Expression Profiling; Goals; Heterogeneity; Homeostasis; Human; Human Herpesvirus 2; Immune; Immune response; Immunity; Immunologics; Immunology; Infection; Intervention; Investigation; Kinetics; Lead; Longevity; Maintenance; Mathematics; Measures; Mediating; Mediator of activation protein; Microscopic; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Outcome; Population; Property; Recording of previous events; Research Personnel; Role; Simplexvirus; Site; Spatial Distribution; System; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Translating; Vaccine Design; Vaccines; Vagina; Viral; Virus; Virus Diseases; Woman; antigen-specific T cells; base; cell mediated immune response; cytokine; design; design verification; experience; experimental study; frontier; genital herpes; human tissue; in silico; mathematical model; mouse model; mucosal site; pathogen; pathogenic virus; protective effect; response; time interval; trafficking

PROJECT SUMMARY The goal of this project is to thoroughly define the immunoprotective role of tissue resident T cells (TRM) against viral pathogens. Underlying our proposed experiments is the idea that TRM have the ability to rapidly contain viruses within microscopic tissue microenvironments over rapid timeframes. Therefore, we focus on critical features of TRM such as gene expression profile, homeostasis, apoptosis and trafficking, before, during and at multiple time points following clearance of a mucosal virus within microscopic sites of infection. In Aim 1, we propose studying the specific role of antigen specific and non-specific tissue resident CD8+ T-cells, as well as tissue resident CD4+ T-cells, during rapid containment of virus in murine vaginal tissue microenvironments. In Aim 2, we interrogate the infection microenvironments in mice following clearance of virus with the specific goal of measuring rates of TRM apoptosis, homeostasis, intra-mucosal trafficking and activation status over time frames of weeks. These parameters will ultimately be evaluated for their relationship to waning protection following re-exposure to virus at various time intervals. In Aim 3, we employ human studies to assess kinetics of genital HSV-2 containment and cytokine response within single infection microenvironments, as well as localization of TRM at multiple time points following viral containment. These studies are designed to verify relevance of specific components of the mouse model to human immunity, and to provide data for design and validation of mathematical models, the goal of which is to identify a threshold quantity and spatial distribution of TRM necessary for rapid viral containment. The model will also help identify why TRM do not provide comprehensive protection against reactivating HSV-2.

项目摘要 该项目的目标是彻底确定组织驻留T细胞（TRM）的免疫保护作用， 病毒病原体。我们提出的实验的基础是TRM有能力快速包含 病毒在微观组织微环境中快速的时间框架。因此，我们专注于关键的 TRM的特征，如基因表达谱，稳态，凋亡和运输，之前，期间和 在显微镜下感染部位清除粘膜病毒后的多个时间点。目标1： 建议研究抗原特异性和非特异性组织驻留CD 8 + T细胞的特定作用，以及 组织驻留的CD 4 + T细胞，在鼠阴道组织微环境中快速遏制病毒期间。在 目的2：探讨特异性抗病毒药物清除病毒后小鼠体内感染微环境的变化。 目标是测量TRM凋亡率、稳态、粘膜内运输和激活状态随时间的变化 周的框架。这些参数最终将被评估为它们与保护减弱的关系 在不同的时间间隔再次暴露于病毒后。在目标3中，我们采用人体研究来评估动力学 生殖器HSV-2遏制和细胞因子反应在单一感染微环境，以及 病毒遏制后多个时间点TRM的定位。这些研究旨在验证 小鼠模型的特定组分与人体免疫力的相关性，并为设计和 数学模型的验证，其目标是确定阈值数量和空间分布， 快速遏制病毒所需的TRM。该模型还将有助于确定为什么TRM不提供 全面的保护，防止HSV-2的重新激活。

项目成果

Heterogeneous SARS-CoV-2 kinetics due to variable timing and intensity of immune responses.

由于免疫反应的时间和强度不同而导致 SARS-CoV-2 动力学异质。

• DOI: 10.1101/2023.08.20.23294350
• 发表时间: 2024
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Owens,Katherine;Esmaeili-Wellman,Shadisadat;Schiffer,JoshuaT
• 通讯作者: Schiffer,JoshuaT

Correlates of protection via modeling.

通过建模关联保护。

• DOI: 10.1038/s43588-022-00221-4
• 发表时间: 2022
• 期刊: Nature computational science
• 作者: Schiffer,JoshuaT

Endogenously Produced SARS-CoV-2 Specific IgG Antibodies May Have a Limited Impact on Clearing Nasal Shedding of Virus during Primary Infection in Humans.

• DOI: 10.3390/v13030516
• 发表时间: 2021-03-20
• 期刊: Viruses
• 作者: Yang S;Jerome KR;Greninger AL;Schiffer JT;Goyal A
• 通讯作者: Goyal A

Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs against Ebola Virus In Vivo.

• DOI: 10.3390/microorganisms9030566
• 发表时间: 2021-03-10
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Finch CL;Dyall J;Xu S;Nelson EA;Postnikova E;Liang JY;Zhou H;DeWald LE;Thomas CJ;Wang A;Xu X;Hughes E;Morris PJ;Mirsalis JC;Nguyen LH;Arolfo MP;Koci B;Holbrook MR;Hensley LE;Jahrling PB;Schmaljohn C;Johansen LM;Olinger GG;Schiffer JT;White JM
• 通讯作者: White JM

Modeling explains prolonged SARS-CoV-2 nasal shedding relative to lung shedding in remdesivir-treated rhesus macaques.

建模解释了相对于Remdesivir处理的恒河猕猴中肺脱落的延长SARS-COV-2鼻脱落。

• DOI: 10.1016/j.isci.2022.104448
• 发表时间: 2022-06-17
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Goyal, Ashish;Duke, Elizabeth R.;Cardozo-Ojeda, E. Fabian;Schiffer, Joshua T.
• 通讯作者: Schiffer, Joshua T.