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

描述（由申请人提供）：疟疾继续在全世界造成显著的发病率和死亡率。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。在恶性疟原虫高传播地区的居民中，自然会发生对严重疾病后果的保护。这种保护作用与反复接触疟疾有关，反复接触疟疾会导致轻度至无症状的感染，而不是发生在非免疫个体中的毁灭性并发症。几十年前的临床观察的基础仍然缺乏特征。我们的小组和其他人已经确定了I型INF反应在疟疾感染中的作用。I型干扰素是一种强有力的免疫调节分子，可以促进效应细胞如NK和T淋巴细胞的活化、分化甚至凋亡，并有利于DC的交叉致敏。因此，我们的工作假设提出，一个更强的I型干扰素在疟疾感染的反应是与一个更具保护性的主机先天性和适应性免疫反应。我们将研究IINF型在轻度疟疾期间的作用，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，并与传播强度相关。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，Daily博士在马拉维ICEMR计划的转录分析方面的专业知识，以在纵向研究中描述轻度疾病儿童的先天性和随后的适应性免疫反应。这一建议将加强马拉维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，因此该提议将提供宿主反应的进一步表征，以告知疾病模型。我们还将讨论如何通过母研究中的疟疾控制干预措施改变传播强度可能会改变宿主反应和疾病表现。最后，这项建议将通过培训马拉维科学家和建设国内疟疾免疫学实验室和科学能力，促进马拉维国际环境监测和研究中心的培训使命。 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，疟疾是世界范围内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，一种强大的免疫调节分子在感染过程中，以及这种反应是否在一个人的重复感染过程中发生变化，改变再感染的风险，并与传播强度相关。研究将为疫苗和预防性治疗提供信息。

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.