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）：疟疾继续在全球引起明显的发病率和死亡率。感染会导致严重威胁生命的疾病，轻度症状或无症状的马车状态。防止严重疾病结局自然发生在高质质质恶性疟原虫传播区域中。该保护与反复的疟疾暴露有关，导致轻度到无症状的运输，而不是在非免疫个体中发生的毁灭性并发症。几十年前进行的这种临床观察的基础仍然很差。我们的小组和其他人在疟疾感染期间确定了I型INF反应的作用。 I型INF被称为强大的免疫调节分子，可以促进效应细胞（例如NK和T淋巴细胞）的激活，分化甚至凋亡，并支持DC的交叉宣传。因此，我们的工作假设提出，在疟疾感染中，I型IFN反应更强与保护性宿主先天和适应性免疫反应有关。我们将检查IINF型在轻度疟疾中的作用，以及这种反应在一个人反复感染期间是否改变，会改变重新感染的风险，并与传播强度有关。该提案带来了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，每日博士通过马拉维ICEMR计划在转录分析方面的专业知识，以表征纵向研究中有轻度疾病儿童的先天和随后的适应性免疫反应。该提案将增强马拉维ICEMR的目标，即了解疟疾疾病的决定因素。宿主免疫反应改变了疟疾疾病的发展，因此该提案将为宿主反应提供进一步的特征，以告知疾病模型。我们还将解决父母研究中通过疟疾控制干预措施通过疟疾控制干预措施的传播强度的变化可能会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在疟疾免疫学领域建立内部实验室和科学能力来进一步进一步实现马拉维ICEMR的培训任务。 公共卫生相关性：该项目调查了与人类疟疾感染相关的免疫反应的特定方面，这是全球发病率和死亡率的主要原因。我们将检查I型干扰素的作用，这是一种强大的免疫调节分子感染过程中的作用，并且这种反应在一个人的重复感染过程中是否会改变，从而改变了重新感染的风险，并且与传播强度有关。研究不适用于疫苗和辅助疗法。