EVOLUTION OF DRUG RESISTANCE IN PLASMODIUM FALCIPARUM

恶性疟原虫耐药性的演变

• 批准号: 6374502
• 负责人: QIN CHENG
• 金额: $ 13.73万
• 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 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374502
• 关键词: Plasmodium falciparum; alternatives to animals in research; antimalarial agents; atovaquone; chloroquine; clearance rate; clinical research; combination chemotherapy; computer simulation; disease /disorder model; drug resistance; epidemiology; geographic site; host organism interaction; human subject; human therapy evaluation; humoral immunity; immune tolerance /unresponsiveness; laboratory mouse; malaria; microorganism antigen; nucleic acid sequence; polymerase chain reaction; surface antigens

DESCRIPTION (Adapted from the Applicant's Abstract): Malaria remains an extremely important infectious disease and the development of drug resistant strains is currently significantly exacerbating the problem. This project will develop stochastic simulation (computer) models that will mimic and predict the growth and spread of malaria in individual infections (in-host) and through communities (populations) in endemic areas. The effects of mutations leading to drug resistance will be specifically examined. The computer models to be developed include "virtual" people and a "virtual" village. Parasites and vector (mosquito) will be programmed to cause and spread infection according to the best current understanding of the factors involved. The approach is based on the hypothesis that the in-host dynamics of chronic malaria infections is dominated by a negative-feedback loop involving the production of successive variant surface antigens, production of antibody to these antigens, the consequent elimination of nearly all parasites with those specific antigens, and the escape of those parasites that have switched to express an alternative surface antigen. This model differs from previous models since it implies a significant genetic bottleneck at the time of antibody clearing of most parasites expressing a particular antigen type. The consequences of this new model are that diverse processes such as the survival of a drug resistant parasite in a single host, the length of time a person remains infected, the degree of diversity of parasites in a single host, the probability of mixed gametocyte infection and therefore the rate of outcrossing, all depend on the switching/recrudescence rate of the parasites. Experimental baselines for the model will be derived in this project by: 1) determining the level of parasitemia which triggers anti-variant surface antibody and the kinetics of production of the antibody; 2) determining the mutation rates to drug resistance of malaria parasites for several drugs; 3) to compare the fitness of drug resistant and mutant parasites; and 4) to examine filed parasite populations and lab isolates for strain specific markers which could provide the basis for strain structuring that would affect the rates at which drug resistance alleles will spread or be lost in a host population.

描述（改编自申请人的摘要）：疟疾仍然是 极为重要的传染病和耐药性的发展 菌株目前正在大大加剧该问题。这个项目将 开发随机模拟（计算机）模型，以模仿并预测 疟疾在个体感染（宿主）和通过 地方性地区的社区（人口）。突变的影响导致 将特别检查耐药性。计算机模型是 开发的包括“虚拟”人和一个“虚拟”村庄。寄生虫和 矢量（蚊子）将被编程以根据 当前对所涉及因素的最佳理解。该方法是基于的 关于慢性疟疾感染的宿内动力学的假设是 由涉及连续产生的负反馈回路主导 变异表面抗原，这些抗原抗体的产生， 因此，用这些特定抗原消除了几乎所有寄生虫， 以及那些转换以表达替代方案的寄生虫的逃脱 表面抗原。该模型与以前的模型不同，因为它暗示了 大多数抗体清除时的遗传瓶颈很大 表达特定抗原类型的寄生虫。这个新的后果 模型是多种过程，例如耐药性的生存 一个宿主中的寄生虫，一个人保持感染的时间长度， 单个宿主中寄生虫的多样性程度，混合的可能性 配子细胞感染，因此脱落的发生率，都取决于 寄生虫的开关/复发率。实验基线 模型将通过以下方式在此项目中得出：1）确定 寄生虫病，可触发抗变体的表面抗体和动力学 产生抗体； 2）确定药物的突变率 多种药物的疟疾寄生虫抗性； 3）比较 耐药和突变寄生虫； 4）检查寄生虫 种群和实验室分离株，用于特定特定标记，可以提供 应变结构的基础，该结构会影响药物的速率 抵抗等位基因将在宿主人群中传播或丢失。