Mechanisms of Nonsterilizing Immunity in Malaria

描述（由申请人提供）：通过免疫或免疫治疗保护人类受试者免受恶性疟原虫血期疟疾的能力需要对抗疟疾免疫反应的理解超出目前已知的范围。虽然在控制血期疟疾的各种免疫途径中存在显著的冗余，但IFNgamma的产生似乎是始终影响抗体介导（AMI）和细胞介导（CMI）对血期寄生虫耐药性的单一因素。从对IFNgamma及其在针对多种病原体的先天和获得性免疫反应的发展和调节中的作用的广泛研究来看，很明显，在IFNgamma的影响下，存在多种途径、细胞群和效应物功能。然而，我们并不完全了解IFNy在通过先天免疫反应、获得性细胞介导的免疫反应、获得性抗体介导的免疫反应控制血期疟疾中的确切作用。同样，我们并不完全了解这些ifnv驱动的反应与宿主抑制血期疟原虫生长的最终能力之间的相互依存关系。我们提出的研究的总体假设是，IFNgamma 1)在导致AMI和CMI的先天免疫反应的早期启动中是必不可少的，2)在适应性免疫反应的效应阶段对CMI的表达是必要的，3)通过抗体介导的效应机制增强对寄生虫病的抑制。我们将通过研究急性恰波迪疟原虫整个过程中的特定免疫细胞群来解决这一假设。具体来说，我们将专注于1)建立IFNgamma产生的动力学，2)确定产生IFNgamma并对IFNgamma作出反应的关键细胞群，以及3)将IFNgamma依赖的免疫效应机制与感染的解决联系起来。在使用P. chabaudi小鼠模型和选择的免疫敲除小鼠中，我们有独特的能力建立不同的IFNgamma依赖途径，导致疟疾期间细胞介导的免疫或抗体介导的免疫。同样重要的是，我们将确定两个保护性反应臂所需的关键IFNgamma依赖性反应。我们坚信，这些研究将大大扩展我们对IFNy驱动抗疟疾免疫反应机制的认识，并确定能够并且应该通过免疫靶向的抗疟疾免疫的ifngamma依赖成分。

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.