Defining the Inflammation and Immunity Transcriptome in Severe Malarial Anemia for Immunotherapeutic Discovery

定义严重疟疾贫血中的炎症和免疫转录组以促进免疫治疗的发现

基本信息

批准号：
10082410
负责人：
Douglas Jay Perkins
金额：
$ 70.77万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-19 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082410
关键词：
Acute Acute Disease Address Aftercare Area Birth Blood specimen Candidate Disease Gene Cessation of life Child Childhood Clinical Clinical Research Clinical Trials County Data Development Disease Disease Progression Drug resistance Erythrocyte Membrane Favorable Clinical Outcome Funding Future Gene Expression Gene Expression Profile Gene Expression Profiling Gene Targeting Genes Genetic Transcription Genomic approach Genotype Goals Health Hemoglobin Immune Immune Response Genes Immune response Immunity Immunotherapeutic agent Immunotherapy Infant Inflammation Inflammatory Investigation Kenya Laboratories Link Longitudinal Studies Malaria Mediating Medical Research Membrane Proteins Metadata Modeling Monitor Morbidity - disease rate Natural Immunity New Mexico Outcome Parasitemia Parasites Pathogenesis Pathway interactions Pattern Pediatric cohort Phenotype Plasmodium falciparum Prognosis Research Institute Risk Risk Assessment Sampling Severities Severity of illness Shapes Testing Therapeutic Agents Translational Research United States National Institutes of Health Universities Vaccines Validation Visit acquired immunity adaptive immunity base biomarker identification co-infection cohort comorbidity density experimental study follow-up genome wide association study global health immunotherapy trials improved malaria infection malarial anemia mortality novel novel strategies novel therapeutic intervention prospective research facility resistant strain therapeutic gene transcriptome transcriptome sequencing transmission process treatment duration whole genome

项目摘要

PROJECT SUMMARY Despite advances in global health, malaria infects 212M and kills 429,000 people annually. Lack of effective vaccines and emergence of drug-resistant strains makes new therapeutic approaches essential. Childhood mortality rates in children <36 months remain exceedingly high in holoendemic Plasmodium falciparum transmission regions such as Siaya, Kenya, due to severe malarial anemia [SMA, hemoglobin (Hb)<5.0 g/dL]. Over the last 14 years, at our state-of-the-art clinical research facilities in Siaya, we focused on how innate immunity and co-morbidities influence clinical outcomes in childhood malaria. Over a three-year follow-up period, we found that 93% of the children had malaria, and 22.7% developed SMA. To identify the most significant pathways that discriminate SMA from milder forms of disease, we spent the last several years using a combination of global genomic approaches to create a convergent model for identification of disease signatures. These studies demonstrated that immune response genes are the strongest predictors for SMA, thus, narrowing the search from the entire genome to pathways involved in the host-immune response. Based on these findings and recent preliminary data, we propose to use targeted RNAseq with a platform that contains of 500 immune response genes (innate and adaptive immunity) which have not been concomitantly explored in malaria. Since our findings demonstrate that the immune response to P. falciparum drives adverse clinical outcomes for several weeks, even after clearance of the parasite, malarial anemia is an ideal candidate for immunotherapy. Thus, the overall goal of the project is to identify critical gene pathways within the transcriptome that mediate disease severity and then target these specific genes with compounds that elicit expression profiles witnessed in children with milder forms of disease. To achieve this goal, we will complete the following specific aims: 1) Determine how changing temporal dynamics of gene pathways in the Malarial Immunity Transcriptome promote SMA during acute disease; 2) Determine how changes in gene pathways in the Malarial Immunity Transcriptome mediate malarial severity throughout the development of naturally- acquired immunity; and 3) Identify immunotherapeutic targets in the Malarial Immunity Transcriptome that can be used to reduce malaria disease severity and improve clinical outcomes in future trials. To successfully complete these aims, we will determine how host and parasitic expression profiles impact on acute disease over 14 days (cohort 1) and validate these findings in a longitudinal birth cohort (cohort 2) during the child's 1st episode of acute malaria. We will also determine the impact of changing host and parasite temporal expression profiles on the development of naturally-acquired immunity over 36 months (cohort 2). Ex vivo samples from the two cohorts will be used to test the effect of immunotherapeutic compounds on host expression profiles. Accomplishing these goals will have broad reaching translational implications for: (1) identifying at-risk groups, and (2) prioritizing compounds that can be used to improve clinical outcomes in future immunotherapy trials.

项目概要尽管全球卫生事业取得了进步，但疟疾每年仍感染 2.12 亿人并导致 429,000 人死亡。缺乏有效的疫苗的出现和耐药菌株的出现使得新的治疗方法变得至关重要。童年在恶性疟原虫恶性疟原虫肆虐的情况下，36 个月以下儿童的死亡率仍然极高肯尼亚西亚亚等传播地区因严重疟疾贫血[SMA，血红蛋白 (Hb)<5.0 g/dL]。在过去的 14 年里，在我们位于 Siaya 的最先进的临床研究设施中，我们专注于先天性如何免疫和合并症影响儿童疟疾的临床结果。经过三年多的随访期间，我们发现93%的儿童患有疟疾，22.7%的儿童患有SMA。来识别最区分 SMA 和较轻疾病的重要途径，我们在过去几年中使用结合全球基因组方法来创建疾病识别的聚合模型签名。这些研究表明，免疫反应基因是 SMA 最强的预测因素，因此，将搜索范围从整个基因组缩小到参与宿主免疫反应的途径。基于根据这些发现和最近的初步数据，我们建议使用靶向 RNAseq 和一个平台，包含 500 个免疫反应基因（先天性免疫和适应性免疫），这些基因尚未同时被在疟疾中进行了探索。由于我们的研究结果表明，对恶性疟原虫的免疫反应会导致不良反应即使在寄生虫被清除后，仍可维持数周的临床结果，疟疾性贫血是理想的候选者用于免疫治疗。因此，该项目的总体目标是确定基因组中的关键基因途径。介导疾病严重程度的转录组，然后用引发的化合物靶向这些特定基因在患有较轻疾病的儿童中观察到了表达谱。为了实现这一目标，我们将完成具体目标如下： 1) 确定疟疾中基因途径的时间动态变化如何免疫转录组在急性疾病期间促进 SMA； 2) 确定基因通路的变化疟疾免疫转录组在自然发育过程中介导疟疾的严重程度获得性免疫力； 3) 确定疟疾免疫转录组中的免疫治疗靶点在未来的试验中可用于降低疟疾疾病的严重程度并改善临床结果。才能成功完成这些目标，我们将确定宿主和寄生虫的表达谱如何影响急性疾病超过 14 天（队列 1），并在孩子第一胎期间的纵向出生队列（队列 2）中验证这些发现急性疟疾发作。我们还将确定改变宿主和寄生虫时间表达的影响 36 个月内自然获得性免疫力发展概况（第 2 组）。离体样本来自这两个队列将用于测试免疫治疗化合物对宿主表达谱的影响。实现这些目标将对以下方面产生广泛的转化影响：(1) 识别高危人群， (2) 优先考虑可用于改善未来免疫治疗试验临床结果的化合物。