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

描述（由申请人提供）：本研究将系统地检查宿主铁状态和铁干预对疟疾寄生虫和/或病原菌感染严重程度的影响。我们将使用强大的感染小鼠模型进行这项研究。在这些研究中，我们选择了啮齿类疟疾种属，伯氏疟原虫和夏氏疟原虫，它们分别代表了一种快速致死的高毒力种属和一种毒力较低的种属，这种种属往往通过获得性免疫来解决，并且更接近于恶性疟原虫感染。这两个物种将使我们能够研究是否在主机铁状态或铁干预的差异可以降低疟疾寄生虫的毒力，或者，加剧疾病和增加毒力。此外，我们将使用鼠伤寒沙门氏菌脓毒症模型，探讨铁的状态和铁的干预措施对疟疾寄生虫和细菌共感染的共同代理人的共感染的影响。这种肠道嗜铁菌是非洲儿童菌血症的主要原因，无论是否患有疟疾。该项目利用了纽约的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和铁生物学模型的专业知识相结合。我们的项目研究这些模型系统中的机制和干预措施，包括三个具体目标： (1)检验膳食缺铁性贫血增加伯氏疟原虫和夏氏疟原虫疟疾以及S.鼠伤寒沙门氏菌，在单独和合并感染。 (2)检验口服铁补充剂增加红细胞期P。 chabaudi疟疾和S.鼠伤寒沙门氏菌，在单独和合并感染，通过增加血浆非转铁蛋白结合铁。 (3)检验补充铁通过增强肝细胞内的增殖而在体内和体外增加伯氏疟原虫感染的肝脏阶段的严重程度的假设。 这些研究将首次系统地检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有效地使用铁干预措施。 公共卫生相关性：这些研究将提供一个系统的检查，铁干预的影响，疟疾和细菌感染的严重程度，在铁充足和缺铁状态，使用良好的表征人类疾病的小鼠模型。研究结果将提供新的证据，帮助指导在地方性疟疾和传染病地区安全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.