Mechanisms of Nonsterilizing Immunity in Malaria

描述（由申请方提供）：通过免疫或免疫治疗保护人类受试者免受恶性疟原虫血液期疟疾的能力需要对目前已知的抗疟疾免疫应答的理解。虽然在控制血液阶段疟疾的各种免疫途径中存在显著的冗余，但IFN γ的产生似乎是持续影响抗体介导（AMI）和细胞介导（CMI）对血液阶段寄生虫的抗性的单一因素。从IFN γ及其在针对不同病原体的先天性和获得性免疫应答的发展和调节中的作用的广泛研究中，很明显，在IFN γ的影响下存在多种途径、细胞群和效应子功能。然而，我们并不完全了解IFN γ在通过先天免疫应答或通过获得性细胞介导的免疫应答、通过获得性抗体介导的免疫应答控制血液期疟疾中的确切作用。同样，我们也没有完全理解这些IFN-γ驱动的反应与宿主抑制血液期疟原虫生长的最终能力之间的相互依赖性。我们提出的研究的总体假设是IFN γ 1）在导致AMI和CMI的先天免疫应答的起始早期是必需的，2）在适应性免疫应答的效应物阶段期间是CMI表达所必需的，和3）通过抗体介导的效应物机制增强寄生虫血症的抑制。我们将通过研究整个急性夏氏疟原虫疟疾过程中免疫细胞的特定群体来实验性地解决这一假设。具体而言，我们将集中于1）建立IFN γ产生的动力学，2）鉴定产生IFN γ并响应IFN γ的关键细胞群，以及3）将IFN γ依赖性免疫效应机制与感染的解决联系起来。在使用P. chabaudi鼠模型和选择的免疫敲除小鼠中，我们具有独特的能力来建立不同的IFN γ依赖性途径，其导致疟疾期间的细胞介导的免疫或抗体介导的免疫。同样重要的是，我们将确定保护性反应的两个臂所需的关键IFN γ依赖性反应。我们坚信，这些研究将显著扩展我们对IFN γ驱动抗疟疾免疫应答的机制的认识，并确定可以并且应该通过免疫靶向的抗疟疾免疫的IFN γ依赖性组分。

DESCRIPTION (provided by applicant): The ability to protect human subjects against Plasmodium falciparum blood-stage malaria by immunization or immunotherapy requires an understanding of anti-malarial immune responses beyond what is currently known. While there is a remarkable redundancy in various immune pathways that control blood-stage malaria, IFNgamma production appears to be the single factor that consistently influences antibody-mediated (AMI) and cell-mediated (CMI) resistance to blood-stage parasites. From extensive studies of IFNgamma and its role in the development and regulation of innate and acquired immune responses against diverse pathogens, it is clear that there are multiple pathways, cell populations and effectors functions under the influence of IFNgamma. However, we do not fully understand the exact role of IFNy in the control of blood-stage malaria by innate immune responses, or by acquired cell-mediated immune responses, by acquired antibody-mediated immune responses. Likewise, we do not fully understand the interdependence of these IFNv-driven responses on the ultimate ability of the host to suppress the growth of blood-stage malaria parasites. The overall hypothesis for our proposed study is that IFNgamma 1) is essential early in the initiation of the innate immune response leading to both AMI and CMI, 2) is necessary for the expression of CMI during the effector phase of the adaptive immune response and 3) enhances the suppression of parasitemia by antibody-mediated effector mechanisms. We will address this hypothesis experimentally by studying specific populations of immune cells throughout the course of acute P. chabaudi malaria. Specifically, we will focus on 1) establishing the kinetics of IFNgamma production, 2) identifying the critical populations of cells producing IFNgamma and responding to IFNgamma and 3) linking IFNgamma dependent immune effector mechanisms to the resolution of infection. In using the P. chabaudi murine model and selected immunologic knockout mice, we have the unique ability to establish the distinct IFNgamma dependent pathways that lead to cell-mediated immunity or to antibody-mediated immunity during malaria. As important, we will identify critical IFNgamma dependent responses required for both arms of the protective response. We firmly believe that these studies will significantly extend our knowledge on the mechanisms by which IFNy drives antimalarial immune responses and identify IFNgamma-dependent components of anti-malaria immunity that can and should be targeted by immunization.