Mechanisms of effect of iron status & interventions on malaria & other infections

描述(申请人提供)：这项研究将系统地研究宿主铁状况和铁干预措施对感染疟疾寄生虫和/或病原菌的严重程度的影响。我们将使用健壮的小鼠感染模型进行这项研究。在这些研究中，我们选择了啮齿动物疟疾物种伯氏疟原虫和查鲍迪疟原虫，它们分别代表了一种快速致死的高毒力物种和一种倾向于通过获得性免疫来解决且更接近于恶性疟原虫感染的毒力较低的物种。这两个物种将使我们能够检验宿主铁状态或铁干预措施的差异是否可以降低疟疾寄生虫的毒力，或者相反，加剧疾病和增加毒力。此外，我们将使用鼠伤寒沙门氏菌败血症模型来探索铁状态和铁干预对疟疾寄生虫和细菌合并感染的共同感染的影响。无论是否患有疟疾，这种嗜铁的肠道细菌都是非洲儿童菌血症的主要原因。该项目利用了纽约哥伦比亚大学独特的资源和专业知识，将研究人员与疟原虫感染模型和铁生物学方面的专业知识结合在一起。我们的项目调查这些模型系统中的机制和干预，包括三个具体目标： (1)检验这样一种假设，即在单独和混合感染中，膳食缺铁性贫血会增加伯氏疟原虫和沙包氏疟原虫以及鼠伤寒沙门氏菌红细胞期的严重程度。 (2)检验口服铁补充剂增加P。 查鲍迪疟疾和鼠伤寒沙门氏菌通过增加血浆非转铁蛋白结合铁，在单独感染和混合感染中的作用。 (3)验证补充铁通过促进肝细胞内增殖来增加体内和体外伯氏肺孢子虫感染肝脏阶段的严重性的假设。 这些研究将首次系统审查铁干预措施对铁充足和缺铁州疟疾和细菌感染的影响，并将有助于指导在疟疾流行地区安全和有效地使用铁干预措施。 与公共卫生相关：这些研究将利用具有良好特征的人类疾病小鼠模型，系统地检查铁干预措施对铁充足和铁缺乏状态下疟疾和细菌感染严重程度的影响。这一结果将提供新的证据，帮助指导在疟疾流行和传染病流行地区安全和有效地使用铁干预措施。

DESCRIPTION (provided by applicant): This research will systematically examine the effects of host iron status and iron interventions on the severity of infection with malarial parasites and/or pathogenic bacteria. We will conduct this research using robust mouse models of infection. For these studies, we selected rodent malarial species, Plasmodium berghei and P. chabaudi, which, respectively, represent a highly virulent species that is rapidly lethal and a less virulent species that tends to be resolved by acquired immunity and that more closely mimics a P. falciparum infection. These two species will enable us to examine whether differences in host iron status or iron interventions can diminish malarial parasite virulence or, alternatively, exacerbate disease and increase virulence. In addition, we will use a Salmonella typhimurium sepsis model to explore the effect of iron status and iron interventions on coinfections of a malarial parasite and a common agent of bacterial coinfection. This ferrophilic enteric species is a leading cause of bacteremia in African children with or without malaria. This project exploits the unique convergence of resources and expertise at Columbia University in New York, combining investigators with expertise in models of Plasmodium infection and iron biology. Our project, which investigates mechanisms and interventions in these model systems, encompasses three Specific Aims: (1) Test the hypothesis that dietary iron deficiency anemia increases the severity of the erythrocytic phases of P. berghei and P. chabaudi malaria and of S. typhimurium, in both separate and combined infections. (2) Test the hypothesis that oral iron supplements increase the severity of the erythrocytic stages of P. chabaudi malaria and of S. typhimurium, in both separate and combined infections, by increasing plasma nontransferrin-bound iron. (3) Test the hypothesis that supplemental iron increases the severity of the hepatic stage of P. berghei infection, both in vivo and in vitro, by enhancing proliferation within hepatocytes. These studies will provide the first systematic examination of the effect of iron interventions on malarial and bacterial infection in iron-replete and iron-deficient states and will help guide the safe and effective use of iron interventions in areas with endemic malaria. PUBLIC HEALTH RELEVANCE: These studies will provide a systematic examination of the effect of iron interventions on the severity of malarial and bacterial infection in iron-replete and iron-deficient states using well-characterized mouse models of human disease. The results will provide new evidence to help guide the safe and effective use of iron interventions in areas of endemic malaria and infectious diseases.