Maintenance vs Programming in Th1 Memory Cell Development in P. Chabaudi Malaria

P. Chabaudi 疟疾中 Th1 记忆细胞发育的维护与编程

基本信息

批准号：
8857363
负责人：
Robin Stephens
金额：
$ 40.33万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8857363
关键词：
Accounting Address Affect Antigens B-Lymphocytes Biological Assay Cell Maintenance Cells Cellular Immunity Cessation of life Chromatin Chromatin Remodeling Factor Chronic Chronic Disease Complement Culicidae Cytokine Receptors Data Development Disease Drug resistance Flow Cytometry Genetic Transcription Goals HIV Hand functions Hepatitis C Human Humanities Immune system Immunity Immunologic Techniques Immunology Infection Inflammation Interferons Knowledge Life Literature Longevity Maintenance Malaria Measurable Memory Merozoite Surface Protein 1 Modeling Molecular Morbidity - disease rate Mus Outcome Parasites Pattern Phase Phenotype Plague Planet Mars Plasmodium chabaudi Population Prevention strategy Production Protocols documentation Research Resistance development Speed Stimulus Symptoms System T memory cell T-Lymphocyte T-Lymphocyte Subsets Techniques Th1 Cells Transgenic Organisms Tuberculosis Vaccination Vaccine Adjuvant Vaccine Design Vaccines Work burden of illness cell type cytokine flexibility in vitro testing in vivo innovation insight killings memory CD4 T lymphocyte novel pathogen pesticide resistance programs research study response treatment strategy vaccination against tuberculosis vaccine development vaccine trial

项目摘要

DESCRIPTION (provided by applicant): Two major hurdles in developing effective vaccines for chronic infections such as HIV, TB and malaria are the lack of knowledge of the critical factors for maintenance of protective immunity, and the lack of a measurable cell type that correlates with protection. To address these gaps in our knowledge, we propose to identify the protective memory T cell subsets in chronic malaria infection and define the mechanisms that they use to survive and maintain protective cytokine production. Our preliminary data demonstrate that malaria- specific T cells differentiate into effector memory cells (Tem), which contribute to protection best if they are exposed to chronic infection. Chronic infection also enhances their Th1 cytokine production (IFN3+), correlating with this protection. Therefore, our central hypothesis is that Tem subsets maintain a protective cytokine program like committed Th1 cells that is maintained by the inflammation associated with chronic infection. The goals of this proposal are therefore to determine which CD4+ memory T cell subsets are protective and survive and which help B cells (T follicular helper, Tfh) or remain committed to the Th1 phenotype. These goals will be achieved by the completion of the following specific aims: 1) To determine protection, survival and effector function (Th1, Tfh) of CD4+ effector memory T cell subsets, and 2) To determine subsets producing IFN3 and their degree of Th1 commitment. The first aim will define protective memory T cell subsets and the factors required for their maintenance and will be accomplished by in vivo protection, survival and cytokine production assays already established as feasible in the applicant's hands, using modern in vivo immunological techniques and multi-parameter flow cytometry. The second aim is firstly to test the in vitro stability of the Th1 cytokine profile of malaria-specific memory cells, using the same techniques I used in my dissertation work, and secondly; to study the indicative pattern of cytokines, cytokine receptors, transcription and chromatin tatistics factors to define mechanisms utilized by Th1 memory cells for maintenance of their effector function in chronic infection. The outcomes of these two aims will allow us to define stimuli used by protective memory CD4+ T cells to survive and the mechanisms to remain protective in chronic infection. Providing knowledge including both novel stimuli to include for a successful vaccination protocol and a memory T cell- type that correlates with protection. The approach is innovative because we have a novel malaria-specific T cell transgenic system, an accurate murine malaria model, using Plasmodium chabaudi; and also because the proposal focuses on effector memory T cells, though others have disregarded them in favor of central memory cells, in spite of evidence of better protection by Tem. This approach to vaccination is supported by evidence that generating and maintaining effector memory cells by vaccination is feasible. The proposed research is significant because the outcomes are directly applicable to malaria, HIV and TB vaccination trials and may speed the search for a protective vaccine to malaria, one of the most lethal infections of mankind.

描述（由申请人提供）：开发针对艾滋病毒、结核病和疟疾等慢性感染的有效疫苗的两个主要障碍是缺乏对维持保护性免疫的关键因素的了解，以及缺乏与免疫相关的可测量细胞类型保护。为了弥补我们知识中的这些空白，我们建议识别慢性疟疾感染中的保护性记忆 T 细胞亚群，并定义它们用于生存和维持保护性细胞因子产生的机制。我们的初步数据表明，疟疾特异性 T 细胞分化为效应记忆细胞 (Tem)，如果它们暴露于慢性感染，则能提供最佳保护。慢性感染还会增强 Th1 细胞因子的产生 (IFN3+)，与这种保护相关。因此，我们的中心假设是，Tem 亚群维持着一种保护性细胞因子程序，就像由慢性感染相关炎症维持的定型 Th1 细胞一样。因此，该提案的目标是确定哪些 CD4+ 记忆 T 细胞亚群具有保护性并存活下来，哪些有助于 B 细胞（滤泡辅助 T，Tfh）或保持 Th1 表型。这些目标将通过完成以下具体目标来实现：1) 确定 CD4+ 效应记忆 T 细胞亚群的保护、存活和效应功能（Th1、Tfh），以及 2) 确定产生 IFN3 的亚群及其 Th1 程度承诺。第一个目标将定义保护性记忆T细胞亚群及其维持所需的因素，并将通过申请人手中已经建立的可行的体内保护、存活和细胞因子产生测定法来实现，使用现代体内免疫学技术和多参数流式细胞术。第二个目标首先是使用我在论文工作中使用的相同技术来测试疟疾特异性记忆细胞的 Th1 细胞因子谱的体外稳定性，其次；研究细胞因子、细胞因子受体、转录和染色质统计因子的指示模式，以确定 Th1 记忆细胞在慢性感染中维持其效应功能的机制。这两个目标的结果将使我们能够定义保护性记忆 CD4+ T 细胞生存的刺激以及在慢性感染中保持保护性的机制。提供知识，包括成功的疫苗接种方案所需的新刺激以及与保护相关的记忆 T 细胞类型。该方法具有创新性，因为我们拥有一种新型的疟疾特异性 T 细胞转基因系统，即使用 Chabaudi 疟原虫的精确小鼠疟疾模型；还因为该提案侧重于效应记忆 T 细胞，尽管其他人忽视了它们，转而支持中央记忆细胞，尽管有证据表明 Tem 提供了更好的保护。这种疫苗接种方法得到了证据的支持，证明通过疫苗接种产生和维持效应记忆细胞是可行的。拟议的研究意义重大，因为其结果直接适用于疟疾、艾滋病毒和结核病疫苗接种试验，并可能加速寻找针对人类最致命的感染之一的疟疾的保护性疫苗。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection.

在持续性疟疾感染中保护和维持 CD4 效应记忆和效应 T 细胞亚群。

DOI：
发表时间：
2018-04
期刊：
影响因子：
6.7
作者：
Opata, Michael M;Ibitokou, Samad A;Carpio, Victor H;Marshall, Karis M;Dillon, Brian E;Carl, Jordan C;Wilson, Kyle D;Arcari, Christine M;Stephens, Robin
通讯作者：
Stephens, Robin

Correction: IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection.

更正：IFN-γ 和 IL-21 双产 T 细胞不依赖于 Bcl6，并在 Chabaudi 疟原虫感染中存活到记忆期。

DOI：
发表时间：
2016
期刊：
影响因子：
3.7
作者：
Carpio, Victor H;Opata, Michael M;Montañez, Marelle E;Banerjee, Pinaki P;Dent, Alexander L;Stephens, Robin
通讯作者：
Stephens, Robin

Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection.

脂肪酸合成的早期抑制可减少慢性感染中记忆前体效应 T 细胞的生成。

DOI：
发表时间：
2018-01-15
期刊：
影响因子：
0
作者：
Ibitokou, Samad A;Dillon, Brian E;Sinha, Mala;Szczesny, Bartosz;Delgadillo, Añahi;Reda Abdelrahman, Doaa;Szabo, Csaba;Abu;Porter, Craig;Tuvdendorj, Demidmaa;Stephens, Robin
通讯作者：
Stephens, Robin

Dissemination of non-typhoidal Salmonella during Plasmodium chabaudi infection affects anti-malarial immunity.

查鲍迪疟原虫感染期间非伤寒沙门氏菌的传播会影响抗疟疾免疫力。

DOI：
发表时间：
2019-07
期刊：
影响因子：
2
作者：
Alamer, Edrous;Carpio, Victor H;Ibitokou, Samad A;Kirtley, Michelle L;Phoenix, Inaia R;Opata, Michael M;Wilson, Kyle D;Cong, Yingzi;Dann, Sara M;Chopra, Ashok K;Stephens, Robin
通讯作者：
Stephens, Robin

Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria.

消除血管内血栓可防止早期死亡并减少高炎症实验性脑疟疾中的神经胶质增生。

DOI：
发表时间：
2018-06-04
期刊：
影响因子：
0
作者：
Wilson, Kyle D;Ochoa, Lorenzo F;Solomon, Olivia D;Pal, Rahul;Cardona, Sandra M;Carpio, Victor H;Keiser, Philip H;Cardona, Astrid E;Vargas, Gracie;Stephens, Robin
通讯作者：
Stephens, Robin