Determinants of Malaria Disease in Malawi, 5U19AIO89683-02 "Competitive Revision"

马拉维疟疾疾病的决定因素，5U19AIO89683-02“竞争性修订”

• 批准号: 8412100
• 负责人: Terrie Ellen Taylor
• 金额: $ 24.97万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8412100
• 关键词: Address; Apoptosis; Carrier State; Cells; Child; Clinical; Complement; Country; Cross-Priming; Dendritic Cells; Development; Disease; Disease Outcome; Disease model; Effector Cell; Genetic Polymorphism; Goals; Human; Immune response; Immunology; Individual; Infection; Interferon Type I; Interferons; Intervention; Laboratories; Leukocytes; Life; Longitudinal Studies; Lymphocyte; Malaria; Malawi; Measures; Memory; Microarray Analysis; Mission; Morbidity - disease rate; Outcome; Parents; Peripheral; Phenotype; Plasmodium falciparum; Research; Risk; Role; Scientist; Source; Symptoms; T memory cell; T-Lymphocyte; Testing; Time; Training; Vaccines; Work; adaptive immunity; base; cell type; cytokine; improved; interferon alpha receptor; microbial; monocyte; mortality; parent grant; pathogen; peripheral blood; programs; response; transmission process

DESCRIPTION (provided by applicant): Malaria continues to cause marked morbidity and mortality worldwide. Infection can result in severe life threatening disease, mild symptoms or an asymptomatic carriage state. Protection from severe disease outcomes naturally occurs in residents high Plasmodium falciparum transmission regions. This protection is related to repeated malaria exposures which result in mild to asymptomatic carriage rather than devastating complications which occur in non-immune individuals. The basis of this clinical observation made decades ago remains poorly characterized. Our group and others have identified a role for type I INF response during malarial infection. Type I INF is known as a powerful immunomodulatory molecule that can promote activation, differentiation or even apoptosis of effector cells such as NK and T lymphocytes and favor cross-priming by DCs. Thus, our working hypothesis proposes that a stronger type I IFN response in malaria infections is associated with a more protective host innate and adaptive immune responses. We will examine the role of type IINF during mild malaria and whether this response changes during repeated infections in one individual, alters the risk of re-infection and is associated with transmission intensity. This proposal brings Dr. Lauvau's expertise in studying immune responses against microbial pathogens, Dr. Daily's expertise in transcriptional analysis with the Malawi ICEMR program to characterize innate and subsequent adaptive immune responses in children with mild disease in a longitudinal study. This proposal will enhance the Malawi ICEMR goals of understanding the determinants of malarial disease. Host immune responses alter the development of malarial disease and thus this proposal will provide a further characterization of host responses to inform disease models. We will also address how changes in transmission intensity through malaria control interventions in the parent study may alter host response and disease presentation. Finally, this proposal will further the training mission of the Malawi ICEMR by training Malawian scientists and building in-country laboratory and scientific capacity in malaria immunology. PUBLIC HEALTH RELEVANCE: This project investigates specific aspects of the immune response associated with malaria infections in humans, a leading cause of morbidity and mortality worldwide. We will examine the role of type I interferon, a powerful immunomodulatory molecule during infection and whether this response changes during repeated infections in one individual, alters the risk of re-infection and is associated with transmission intensity. Studies ill inform vaccine and adjunctive therapy.

描述(申请人提供)：疟疾继续在全世界造成显着的发病率和死亡率。感染可导致严重的危及生命的疾病、轻微的症状或无症状的携带状态。对严重疾病后果的保护自然发生在居民恶性疟高传播区。这种保护与反复接触疟疾有关，这会导致轻微到无症状的携带者，而不是发生在非免疫者身上的毁灭性并发症。几十年前的这一临床观察的基础仍然很不典型。我们小组和其他人已经确定了I型干扰素反应在疟疾感染中的作用。I型干扰素是一种强大的免疫调节分子，可促进NK、T淋巴细胞等效应细胞的活化、分化甚至凋亡，有利于DC的交叉激发。因此，我们的工作假说提出，疟疾感染中较强的I型干扰素反应与更具保护性的宿主先天和适应性免疫反应有关。我们将研究IINF类型在轻度疟疾中的作用，以及这种反应是否在一个人重复感染期间发生变化，改变再次感染的风险，并与传播强度有关。这项建议带来了劳沃博士在研究针对微生物病原体的免疫反应方面的专业知识，以及戴伊博士在马拉维ICEMR计划转录分析方面的专业知识，以在一项纵向研究中表征患有轻度疾病的儿童的先天和随后的获得性免疫反应。这项提议将加强马拉维国际经济、经济、社会和文化权利国际中心关于了解疟疾决定因素的目标。宿主免疫反应改变了疟疾的发展，因此，这一提议将提供宿主反应的进一步特征，为疾病模型提供信息。我们还将在母体研究中通过疟疾控制干预措施解决传播强度的变化如何改变宿主反应和疾病表现。最后，这项提议将通过培训马拉维科学家和建设疟疾免疫学国内实验室和科学能力，进一步推动马拉维国际经济、社会和文化权利国际中心的培训任务。 公共卫生相关性：该项目调查与人类疟疾感染相关的免疫反应的具体方面，疟疾感染是全球发病率和死亡率的主要原因。我们将研究I型干扰素的作用，I型干扰素是感染期间的一种强大的免疫调节分子，以及这种反应是否在一个人反复感染期间发生变化，改变再次感染的风险，并与传播强度有关。研究将为疫苗和辅助治疗提供信息。