Antigenic Variation and Drug Resistance In P. falciparum

恶性疟原虫的抗原变异和耐药性

• 批准号: 6818503
• 负责人: QIN CHENG
• 金额: $ 15.9万
• 依托单位: QUEENSLAND INSTITUTE OF MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818503
• 关键词: Plasmodium falciparum; antigen antibody reaction; antimalarial agents; clinical research; computer simulation; drug resistance; gene expression; genetic strain; geographic difference; host organism interaction; human subject; laboratory mouse; malaria; patient oriented research; population genetics; protozoal antigen; protozoal genetics; surface antigens

DESCRIPTION (provided by the applicant): The development and spread of drug resistance in malaria parasites has become a major obstacle in the treatment and control of the disease that causes approximately 300 million infections and up to 3 million deaths per-year. A better understanding of factors that influence the emergence and survival of drug resistant parasites will help develop intervention strategies that minimize the risk of drug resistance and prolong the effective life of anti-malarial drugs. The ability for P. falciparum parasites to vary the surface protein, PfEMP1, antigenically is important for immune evasion and pathogenesis. PfEMP1, which is encoded by the var genes, allows the parasitized cells to adhere to the linings of blood vessels thereby avoiding destruction by the spleen. PfEMP1 also stimulates a host specific antibody response that kills parasites expressing the protein, while parasites that have switched to express a different variant survive. We hypothesize that antigenic variation of PfEMP1 also plays an important role in the survival and spread of drug resistant malaria parasites. This proposal aims to investigate the process involved in PfEMP1 antigenic variation, the switch rates of these antigens, and the role that PfEMP1 switching and the corresponding host anti-PfEMP1 responses play in the emergence, evolution, maintenance and spread of drug resistance in Plasmodium falciparum. We will use experimental procedures and mathematical simulation models to investigate: 1) Investigate antigenic variation and its role in parasite survival by examining the var gene switching process and associated switch rates in P. falciparum parasites from ex vivo samples of defined strains and from various regions of the world. 2) Investigate the transcribed var genes in parasite populations of pre-treatment and post-treatment recrudescence's to provide experimental proof for the role of antigenic switching in the survival of drug resistant parasites causing treatment failures. 3) Investigate the role of PfEMP1 in determining the parasite population and spread of drug resistance by examining the linkage between PfEMP1 and drug resistance markers in field isolates. 4) Investigate the importance of factors such as antigenic variation, parasite diversity and treatment strategies for the establishment and spread of drug resistant parasite populations within communities, by modeling in-host dynamics and transmission. The outcome of this research will help to develop intervention strategies that minimize the risk of drug resistance and prolong the effective life of anti-malarial drugs. The project has the potential to benefit the health of a substantial proportion of the world's population.

描述（由申请人提供）：疟疾寄生虫耐药性的发展和传播已成为对疾病的治疗和控制的主要障碍，该疾病会引起约3亿次感染，每年最多300万人死亡。更好地理解影响耐药寄生虫的出现和存活的因素，将有助于制定干预策略，以最大程度地减少耐药性的风险并延长抗疟疾药物的有效寿命。 恶性疟原虫寄生虫改变表面蛋白PFEMP1的能力对免疫逃避和发病机理很重要。由VAR基因编码的PFEMP1允许寄生的细胞粘附在血管的衬里上，从而避免脾脏破坏。 PFEMP1还刺激了宿主特定的抗体反应，该抗体反应杀死表达蛋白质的寄生虫，而转换以表达不同变异的寄生虫生存。我们假设PFEMP1的抗原变异在耐药性疟疾寄生虫的存活和传播中也起着重要作用。 该提案旨在调查PFEMP1抗原变异，这些抗原的开关速率以及PFEMP1切换的作用以及相应的宿主抗PFEMP1反应在疟原虫质量疟原虫中耐药性的出现，进化，维持和耐药性。我们将使用实验程序和数学模拟模型进行研究： 1）通过检查来自定义菌株和世界各个区域的体内样本中的恶性疟原虫寄生虫中的VAR基因开关过程和相关的开关速率来研究抗原变异及其在寄生虫存活中的作用。 2）研究在治疗前和治疗后复发的寄生虫种群中的转录VAR基因，以提供实验证明抗原转换在抗药性寄生虫生存中的作用，从而导致治疗失败。 3）研究PFEMP1在确定PFEMP1与耐药性标志物在野外分离株中的连接的作用在确定抗药性的传播中。 4）研究通过对抗原变异，寄生虫多样性和治疗策略等因素的重要性来建立和传播社区内部抗药性寄生虫种群，通过对宿主内动态和传播进行建模。 这项研究的结果将有助于制定干预策略，以最大程度地减少耐药性的风险并延长抗疟疾药物的有效寿命。该项目有可能使世界人口中很大一部分人口的健康受益。