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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：
10375511
负责人：
Joana Carneiro da Silva
金额：
$ 59.29万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375511
关键词：
Address Adult Animal Model Antigens Antimalarials Biological Assay Blood Cells Cessation of life Child Clinical 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 base 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 parasitism programs sex single-cell RNA sequencing small molecule subcutaneous 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，但寄生虫病仍然是导致世界范围内的死亡率和发病率。仅疟疾寄生虫和蠕虫一项就造成了超过一半的每年有10亿临床感染，世界上一半的人口处于危险之中。在这里，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局，重点是混合感染和宿主性别的影响。而联合- 感染多寄生虫是常见的，多寄生虫对疾病传播的后果人们对结果仍然知之甚少。我们将使用单细胞基因表达分析来研究药物治疗以及与多种疟原虫的混合感染会影响寄生虫的传播从宿主到蚊子，使用非人类灵长类动物模型。使用基因组学和基因组学的组合转录组学方法，我们将表征血吸虫持续感染对宿主对儿童疟疾感染的免疫应答，调查其是否发挥免疫调节作用血吸虫病是长期的，它决定了它是否会影响感染疟疾的基因寄生虫。最后，我们将使用动物模型来研究宿主性别和感染部位对丝虫的发展及其对宿主雄性不同药物疗效的推定后果和雌性。这些多学科的研究代表着在量化表征方面的第一步混合感染在寄生虫感染结局中的作用以及在寄生虫寄主性别偏见调查中的作用感染研究。这两个主题的研究严重不足，但却影响着全球数百万人。这个这些发现的意义可能是广泛的，包括研究寄生虫感染的新方法。以及人类和动物模型中的混合感染，以及对免疫和公共卫生的见解高度优先寄生虫病的治疗方法。