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

铁状态的影响机制

• 批准号: 8312476
• 负责人: STEVEN L SPITALNIK
• 金额: $ 18.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312476
• 关键词: Address; African; Area; Bacteremia; Bacterial Infections; Binding; Biological Models; Biology; Child; Communicable Diseases; Data; Dietary Iron; Disease; Enteral; Erythrocytes; Hepatic; Hepatocyte; Immune; In Vitro; Infection; Intervention; Iron; Iron deficiency anemia; Malaria; Modeling; New York; Oral; Outcome Measure; Parasites; Phase; Plasma; Plasmodium berghei; Plasmodium falciparum; Principal Investigator; Research; Research Personnel; Resources; Rodent; Salmonella typhimurium; Sepsis; Severities; Staging; Testing; Universities; Virulence; Virulent; acquired immunity; cytokine; human disease; in vivo; iron supplement; mouse model; pathogenic bacteria; public health relevance; response

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.

描述（由申请人提供）：这项研究将系统地检查宿主铁状态和铁干预措施对疟疾寄生虫和/或致病细菌感染严重程度的影响。我们将使用强大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，berghei和P. chabaudi，它们分别代表了一种高度毒性的物种，它是迅速致死的，并且是一种毒性较低的物种，倾向于通过获得的免疫力解决，并且更加闭合地模拟了恶性疟原虫感染。这两个物种将使我们能够检查宿主铁状态或铁干预措施的差异是否会降低疟疾寄生虫的毒力，或者，或者加剧疾病并增加毒力。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共同感染的影响和细菌共感染的常见药物。这种嗜力肠道物种是患有或没有疟疾的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的资源和专业知识的独特融合，将研究人员与疟原虫感染模型和铁生物学模型相结合。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： （1）检验以下假设：饮食中的铁缺乏症增加了伯格（P. （2）检验以下假设：口服铁补充剂增加了P的红细胞阶段的严重程度。 Chabaudi疟疾和鼠伤寒沙门氏菌在单独的和联合感染中，通过增加血浆非转铁蛋白结合的铁。 （3）检验以下假设，即补充铁通过增强肝细胞内的增殖，从而增加了体内和体外的P. berghei感染的严重程度。 这些研究将对铁养成和铁缺陷型状态中铁干预措施对疟疾和细菌感染的影响进行首次系统检查，并将有助于指导特有疟疾地区的铁干预措施的安全有效使用。 公共卫生相关性：这些研究将对铁养成型和铁缺陷态在铁质和铁缺陷状态中使用良好特征的人类疾病的模型中对铁干预对疟疾和细菌感染的严重程度的影响进行系统的检查。结果将提供新的证据，以帮助指导特有疟疾和传染病地区的铁干预措施的安全有效使用。

项目成果

Transfusion of stored blood impairs host defenses against Gram-negative pathogens in mice.

• DOI: 10.1111/trf.12712
• 发表时间: 2014-11
• 期刊: Transfusion
• 影响因子: 2.9
• 作者: Prestia K;Bandyopadhyay S;Slate A;Francis RO;Francis KP;Spitalnik SL;Fidock DA;Brittenham GM;Hod EA
• 通讯作者: Hod EA

Effect of dietary iron on fetal growth in pregnant mice.

膳食铁对怀孕小鼠胎儿生长的影响。

• 发表时间: 2013
• 期刊: Comparative medicine
• 影响因子: 0.8
• 作者: Hubbard,AndreaC;Bandyopadhyay,Sheila;Wojczyk,BoguslawS;Spitalnik,StevenL;Hod,EldadA;Prestia,KevinA
• 通讯作者: Prestia,KevinA