Understanding immune regulation in blood-stage malaria

摘要 疟疾仍然是影响40%人类的全球健康负担。尽管蚊帐和抗疟药 药物降低了疟疾的发病率和严重程度，每年仍有约2亿病例以高发病率发生 撒哈拉以南非洲儿童死亡率。此外，一线药物治疗现在受到以下威胁 抗药性寄生虫的传播。因此，需要有效疫苗和疗法的新方法。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理解 允许慢性和复发性血液期感染。我们使用啮齿动物疟疾模型来评估细胞 慢性血液期感染患者外周血中CD4T、B细胞应答的动态变化 将这些发现与生活在流行地区的人类进行了比较。这些研究表明，Tregs，它在 人类和啮齿动物在血液期疟疾期间，都会干扰传统的辅助性T细胞(Th)反应和 卵泡辅助性T细胞：生发中心的B细胞伙伴关系。重要的是， Tregs发生在感染后先前未被识别但关键的时间窗口中，以阻碍保护性 豁免权，通过CTLA-4。精确的定时靶向Tregs或CTLA-4增强免疫反应， 加速清除，并产生对血液期疟疾的超越免疫力的物种。因此，我们的 初步数据揭示了与血液期疟疾相关的免疫抑制的关键机制。一个 充分了解血液期疟疾免疫功能低下的细胞和分子基础是 这项竞争性续订申请的长期目标。我们将通过以下具体措施来解决这些问题 目标：SA 1：确定精确定时的Treg耗竭和CTLA-4阻断如何影响疟疾特异性T细胞 细胞和B细胞的反应，以促进清除原发血液期感染。SA 2：确定如何 精确定时Treg耗尽和/或CTLA-4阻断对疟疾特异性记忆T细胞和B细胞的影响 促进物种超越对继发性血液期感染的控制的反应。SA 3：剖析 抑制性途径和细胞如何以及何时限制原发感染的清除并防止发生 超越二次感染控制的物种。

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.