Genomic Studies of the Impact of External Factors on Parasite Development and Disease Outcome

外部因素对寄生虫发育和疾病结果影响的基因组研究

基本信息

批准号：
10597153
负责人：
Joana Carneiro da Silva
金额：
$ 111.53万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597153
关键词：
Address Adult Animal Model Antigens Antimalarials Biological Assay Blood Cells Cessation of life Child Clinical Collecting Cell Communicable Diseases Culicidae Development Disease Disease Outcome Female Filariasis Gender Gene Expression Gene Expression Profiling Genes Genetic Genomics Genotype Gerbils Helminths High-Throughput Nucleotide Sequencing Human Immune response Immunization Immunologic Markers Incidence Infection Investigation Lead Malaria Methods Modeling Molecular Morbidity - disease rate Nematoda Outcome Parasites Parasitic Diseases Parasitic infection Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacotherapy Plasmodium Plasmodium falciparum Plasmodium falciparum genome Population Populations at Risk Prevention strategy Public Health RNA Interference Regulatory Pathway Research Role Schistosoma Schistosoma haematobium Schistosomiasis Scientist Seasons Severities Sex Bias Sex Differentiation Site Stimulus Technology Vaccination co-infection cross immunity differential expression disability disease transmission drug discovery drug efficacy experimental study field study helminth infection human model immunoregulation improved in vivo insight intraperitoneal malaria infection malaria transmission male mortality multidisciplinary neglected tropical diseases nonhuman primate novel strategies novel therapeutics programs sex single-cell RNA sequencing small molecule subcutaneous therapeutic target tool transcriptome sequencing transcriptomics transmission process

项目摘要

Despite significant progress in recent decades, parasitic diseases remain among the principal causes of mortality and morbidity worldwide. Malaria parasites and helminths alone are responsible for more than half a billion clinical infections every year, with half of the world’s population at risk. Here, we propose experiments aimed at using state-of-the-art genomic technologies to address the impact of external factors on parasite development and disease outcome, with an emphasis on the influence of co-infection and host sex. While co- infections with multiple parasites are common, the consequences of poly-parasitism on disease transmission and outcomes remain poorly understood. We will use single-cell gene expression analyses to examine how drug treatment, as well as co-infections with multiple Plasmodium parasites, influence parasite transmission from hosts to mosquitoes, using a non-human primate model. Using a combination of genomics and transcriptomics methods, we will characterize the effect of ongoing Schistosoma haematobium infection on the host immune response to malaria infection in children, investigate if the immunomodulation exerted by schistosomiasis is long-lasting, and determine whether it impacts the genotype of the infecting malaria parasites. Finally, we will use an animal model to investigate the impact of host sex and site of infection on the development of filarial nematodes, and its putative consequences on differential drug efficacy in host males and females. These multi-disciplinary studies represent an initial step in the quantitative characterization of the role of co-infection on the outcome of parasitic infections, and in the investigation of host sex biases in parasitic infection studies. These two topics are critically understudied and yet impact millions of people worldwide. The implications of these findings could be wide-ranging, and include novel approaches to study parasitic infection and co-infections in human and animal models, as well as public health insights into immunization and treatment approaches in high-priority parasitic diseases.

尽管近几十年来取得了重大进展，但寄生虫病仍然是造成疟疾的主要原因之一。仅疟疾寄生虫和蠕虫就造成了全世界一半以上的死亡率和发病率。每年有 10 亿人临床感染，世界上一半的人口面临风险，在此，我们建议进行实验。旨在利用最先进的基因组技术来解决外部因素对寄生虫的影响发展和疾病结果，重点是同时感染和宿主性别的影响。多种寄生虫感染很常见，多种寄生虫对疾病传播的影响我们对结果仍知之甚少，我们将使用单细胞基因表达分析来研究如何进行。药物治疗以及多种疟原虫寄生虫的合并感染会影响寄生虫的传播使用非人类灵长类动物模型结合基因组学和蚊子。转录组学方法，我们将描述持续的埃及血吸虫感染对宿主对儿童疟疾感染的免疫反应，调查是否通过免疫调节发挥作用血吸虫病是长期存在的，并确定它是否影响感染性疟疾的基因型最后，我们将使用动物模型来研究宿主性别和感染部位对寄生虫的影响。丝虫线虫的发育及其对男性宿主不同药物疗效的推定影响这些多学科研究代表了定量表征的第一步。共同感染对寄生虫感染结果的作用，以及在寄生虫感染宿主性别偏见的调查中这两个主题尚未得到充分研究，但却影响着全世界数百万人。这些发现的影响可能是广泛的，包括研究寄生虫感染的新方法人类和动物模型中的混合感染，以及对免疫接种和公共卫生的见解高优先级寄生虫病的治疗方法。