Mechanisms of Nonsterilizing Immunity in Malaria

描述(由申请人提供)：通过免疫或免疫疗法保护受试者免受恶性疟原虫血液期疟疾侵袭的能力，需要对抗疟疾免疫反应的了解超出目前已知的范围。虽然控制血期疟疾的各种免疫途径存在显著的冗余，但干扰素-γ的产生似乎是持续影响抗体介导的(AMI)和细胞介导的(CMI)对血期寄生虫的抵抗力的单一因素。通过对IFNGamma及其在针对不同病原体的先天性和获得性免疫反应的发育和调节中的作用的广泛研究，可以清楚地看到，在IFNGamma的影响下，存在着多种途径、细胞群体和效应器功能。然而，我们还不完全了解IFNy通过先天免疫反应或通过获得性细胞介导的免疫反应、通过获得性抗体介导的免疫反应在控制血液期疟疾中的确切作用。同样，我们也不完全了解这些由IFNv驱动的反应对宿主抑制血液期疟疾寄生虫生长的最终能力的相互依赖。我们提出的研究的总体假设是：1)在导致AMI和CMI的先天免疫反应的启动早期是必不可少的，2)在适应性免疫反应的效应阶段对CMI的表达是必需的，3)通过抗体介导的效应机制增强对寄生虫血症的抑制。我们将通过研究急性沙鲍迪疟原虫过程中的特定免疫细胞群来实验解决这一假说。具体地说，我们将专注于1)建立IFNGamma产生的动力学，2)识别产生IFNGamma并对IFNGamma作出反应的关键细胞群体，以及3)将IFNGamma依赖的免疫效应机制与感染的解决联系起来。在使用查鲍迪疟原虫小鼠模型和选定的免疫学基因敲除小鼠时，我们具有独特的能力来建立独特的IFNGamma依赖途径，从而在疟疾期间导致细胞介导免疫或抗体介导免疫。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的IFNGamma依赖反应。我们坚信，这些研究将极大地扩展我们关于IFNy驱动抗疟疾免疫反应的机制的知识，并确定可以而且应该成为免疫目标的抗疟疾免疫中依赖IFNGamma的成分。

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.