MECHANISMS OF NONSTERILIZING IMMUNITY IN MALARIA

在世界上的许多艺术中，疟疾发病率和死亡率继续不受控制。随着开发有效疫苗的努力增加，很明显，人们对介导抑制受感染宿主寄生虫血症的免疫机制知之甚少。针对疟疾的细胞免疫(CMI)和抗体介导的免疫(AMI)都依赖于CD4+Alphabeta T细胞的激活。这项建议的目的是在缺乏特定分子基因的新型基因敲除(KO)小鼠模型中，检测不同的T细胞激活信号在针对血液期P-Chabaudi疟疾的保护性免疫发展中的作用。要检测的激活信号是通过IL-2受体激活CD4+T辅助细胞的细胞因子、致炎细胞因子(干扰素-γ、IL-12和肿瘤坏死因子α)、共刺激分子(CD40L和CD28)和T细胞受体(TCRalphabeta和TCRGammazeta)。待评估的免疫参数包括寄生虫血症、感染结局、淋巴细胞亚群扩大、激活标志物的表达、细胞因子和巨噬细胞激活标志物的产生、细胞因子的产生和巨噬细胞的激活。沙鲍迪原虫血症通过细胞介导或抗体免疫机制被抑制，从而为评估激活信号的功能提供了机会，KO小鼠仅限于通过CMI或AMI抑制寄生虫血症。KO小鼠感染沙鲍迪疟原虫为研究这些信号提供了一个很好的模型，因为它允许解剖调节AMI和CMI参与的控制信号，这两个信号都参与了对这种小鼠疟疾寄生虫和人类恶性疟原虫的保护性免疫。这项拟议的研究结果将提供预测感染结局的T细胞和巨噬细胞激活情况，并揭示免疫的细胞和分子机制，可能作为免疫预防和/或免疫治疗的靶点。

malaria morbidity and mortality continue to go unchecked in many arts of the world. As efforts mount to develop an effective vaccine, it is readily apparent that little is know regarding the immune mechanisms mediating suppression of parasitemia in the infected host. Both cell- mediated immunity (CMI) and antibody-mediated immunity (AMI) against malaria are dependent upon the activation of CD4+alphabeta T cells. The goal of this proposal is to examine the function of different T cell activating signals on the development of protective immunity against blood-stage P chabaudi malaria in the novel model of knockout (KO) mice lacking genes for the particular molecule being studied. The activating signals to be examined are cytokines activating CD4+T helper cells through the IL-2 receptor, proinflammator cytokines (IFN-gamma, IL-12 and TNFalpha), co-stimulatory molecules (CD40L and CD28) and T cell receptors (TCRalphabeta and TCRgammazeta). The parameters of immunity to be assessed are parasitemia, outcome of infection, expansion of lymphocyte subsets, expression of activation markers, production of cytokines and macrophage activation markers, production of cytokines and macrophage activation. P. Chabaudi parasitemia is suppressed by cell- mediated or antibody mechanisms of immunity thereby providing the opportunity to evaluate the function of activating signals in KO mice limited to suppressing parasitemia by either CMI or AMI. P. Chabaudi infection of KO mice provides an excellent model for studying these signals because it allows dissecting of the controlling signals that regulate the participation of AMI and CMI, both of which participate in protective immunity against both this murine malarial parasite and human P. Falciparum. The results of this proposed research will provide profiles of T cell and macrophage activation predictive of the out come of infection and reveal the cellular and molecular mechanisms of immunity that may serve as targets for immunoprophylaxis and/or immunotherapy.