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

描述（由申请人提供）：本研究将系统地研究宿主铁状态和铁干预对疟疾寄生虫和/或致病菌感染严重程度的影响。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的疟疾物种，伯氏疟原虫和沙巴蒂疟原虫，它们分别代表了一种高毒力的物种，可以迅速致死，而一种弱毒的物种往往通过获得性免疫来解决，更接近于恶性疟原虫感染。这两个物种将使我们能够检查宿主铁状态的差异或铁干预是否可以减少疟疾寄生虫的毒力，或者加重疾病和增加毒力。此外，我们将使用鼠伤寒沙门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共感染的共同感染的影响。这种嗜铁肠道菌种是非洲患有或未患疟疾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的专业知识结合起来。我们的项目研究了这些模型系统中的机制和干预措施，包括三个具体目标：

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.