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（由申请人提供）：疟疾继续在全世界造成显着的发病率和死亡率。感染可导致严重危及生命的疾病、轻微症状或无症状携带状态。在恶性疟原虫传播高的地区，居民自然会免受严重疾病后果的影响。这种保护作用与反复接触疟疾有关，后者会导致轻微至无症状的携带，而不是在非免疫个体中发生的破坏性并发症。几十年前进行的这一临床观察的基础仍然知之甚少。我们的小组和其他人已经确定了 I 型 INF 反应在疟疾感染期间的作用。 I型INF被认为是一种强大的免疫调节分子，可以促进NK和T淋巴细胞等效应细胞的激活、分化甚至凋亡，并有利于DC的交叉启动。因此，我们的工作假设提出，疟疾感染中更强的 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相关。我们将研究 IINF 型在轻度疟疾期间的作用，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以及与传播强度相关。该提案将 Lauvau 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、Daily 博士在转录分析方面的专业知识与马拉维 ICEMR 计划结合起来，以在纵向研究中描述患有轻度疾病的儿童的先天性和随后的适应性免疫反应。该提案将增强马拉维 ICEMR 了解疟疾疾病决定因素的目标。宿主免疫反应改变疟疾疾病的发展，因此该提案将提供宿主反应的进一步表征，为疾病模型提供信息。我们还将讨论母研究中通过疟疾控制干预措施传播强度的变化如何可能改变宿主反应和疾病表现。最后，该提案将通过培训马拉维科学家并建设国内疟疾免疫学实验室和科学能力，进一步推进马拉维 ICEMR 的培训使命。 公共卫生相关性：该项目研究与人类疟疾感染相关的免疫反应的具体方面，疟疾是全世界发病和死亡的主要原因。我们将研究 I 型干扰素（一种强大的免疫调节分子）在感染过程中的作用，以及这种反应在一个人重复感染期间是否会发生变化、改变再次感染的风险以及与传播强度相关。研究为疫苗和辅助治疗提供了信息。