Understanding immune regulation in blood-stage malaria

了解血期疟疾的免疫调节

基本信息

批准号：
10192639
负责人：
John T Harty
金额：
$ 43.38万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192639
关键词：
Address Africa South of the Sahara Antibody Response Antimalarials Area Artemisinins B-Lymphocytes Beds Blood CD4 Positive T Lymphocytes CTLA4 gene Cell Compartmentation Cells Cessation of life Child Chronic Clinical Trials Data Development Disease Dissection Event FDA approved Failure Generations Goals Human Humoral Immunities Immune Immune response Immunity Immunosuppression Incidence Infection Insecticides Intervention Liver Malaria Malaria Vaccines Memory B-Lymphocyte Modeling Molecular Parasite resistance Parasites Pathway interactions Pharmacotherapy Plasmodium Plasmodium falciparum Population Primary Infection Regulatory T-Lymphocyte Research Rodent Severities Southeastern Asia Structure of germinal center of lymph node T cell response T memory cell T-Lymphocyte Therapeutic Transcend Vaccines adaptive immunity base cancer therapy exhaust global health immune checkpoint blockade immunoregulation improved malaria infection mortality novel strategies prevent response secondary infection

项目摘要

Abstract Malarial remains a global health burden that impacts >40% of humans. Although bed nets and antimalarial drugs have reduced the incidence and severity of malaria, ~200,000,000 cases still occur annually with high mortality in children from sub-Saharan Africa. Additionally, front line drug therapies are now threatened by spread of resistant parasites. Thus, new approaches to effective vaccines and therapeutics are in need. A critical limitation is our incomplete understanding of how the parasite manipulates host immune responses to permit chronic and recurring blood-stage infections. We used rodent malaria models to evaluate the cellular dynamics of the CD4 T cell and B cell responses generated during chronic blood-stage infection and then compared these findings to humans living in endemic areas. These studies reveal that Tregs, which expand in both humans and rodents during blood-stage malaria, interfere with conventional T helper (Th) responses and the Follicular T helper (Tfh) cell:B cell partnership in germinal centers. Importantly, the negative impact of Tregs occurs in a previously unrecognized but critical temporal window after infection to impede protective immunity, through CTLA-4. Precisely timed targeting of Tregs or CTLA-4 enhanced immune responses, accelerated clearance, and generated species-transcending immunity to blood-stage malaria. Thus, our preliminary data uncover a critical mechanism of immune-suppression associated with blood-stage malaria. A full understanding of the cellular and molecular basis for compromised immunity in blood-stage malaria is the long-term goal of this competitive renewal application. We will address these issues with the following specific aims: SA 1: Determine how precisely timed Treg-depletion and CTLA-4 blockade impacts malaria-specific T cell and B cell responses to facilitate clearance of PRIMARY blood-stage infections. SA 2: Determine how precisely timed Treg-depletion and/or CTLA-4 blockade impacts malaria-specific memory T cell and B cell responses to facilitate species transcending control of SECONDARY blood-stage infections. SA 3: Dissect how and when inhibitory pathways and cells limit clearance of PRIMARY infection and prevent development of species transcending control of SECONDARY infections.

抽象的疟疾仍然是全球健康负担，影响超过 40% 的人类。尽管蚊帐和抗疟药药物已降低了疟疾的发病率和严重程度，但每年仍会发生约 2 亿例疟疾，发病率很高撒哈拉以南非洲儿童死亡率。此外，前线药物疗法现在受到以下威胁：耐药寄生虫的传播。因此，需要新的有效疫苗和治疗方法。一个关键的限制是我们对寄生虫如何操纵宿主免疫反应的不完全了解允许慢性和复发性血液阶段感染。我们使用啮齿动物疟疾模型来评估细胞慢性血液阶段感染期间产生的 CD4 T 细胞和 B 细胞反应的动力学，然后将这些发现与生活在流行地区的人类进行比较。这些研究表明，Tregs 在人类和啮齿类动物在血期疟疾期间都会干扰常规 T 辅助细胞 (Th) 反应，滤泡 T 辅助细胞 (Tfh) 细胞：生发中心的 B 细胞伙伴关系。重要的是，负面影响 Tregs 发生在感染后一个先前未被识别但关键的时间窗口，以阻碍保护性免疫，通过 CTLA-4。精确定时靶向 Tregs 或 CTLA-4 增强免疫反应，加速清除，并产生了对血期疟疾的跨物种免疫力。因此，我们的初步数据揭示了与血期疟疾相关的免疫抑制的关键机制。一个充分了解血期疟疾免疫力受损的细胞和分子基础是此竞争性续订应用程序的长期目标。我们将通过以下具体措施解决这些问题目标：SA 1：确定定时 Treg 消耗和 CTLA-4 阻断如何影响疟疾特异性 T 细胞和 B 细胞反应，以促进原发性血液阶段感染的清除。 SA 2：确定如何精确定时的 Treg 耗竭和/或 CTLA-4 阻断会影响疟疾特异性记忆 T 细胞和 B 细胞促进物种超越二级血液阶段感染控制的反应。 SA 3：解剖抑制途径和细胞如何以及何时限制原发感染的清除并防止发展超越二次感染控制的物种。