Epidemiology and molecular mechanisms of anthelminthic treatment failure in Kinta

描述（由申请人提供）：大约有10亿人感染钩虫（美洲钩虫和十二指肠钩虫），这是全球贫血和营养不良的主要原因。撒哈拉以南非洲的全球钩虫感染率最高（29%）。感染是造成严重发病率的原因，包括在受感染儿童中观察到的认知能力和生长障碍。弱势群体还包括孕妇。证据还表明，慢性低强度钩虫感染可能损害控制其他热带疾病的能力，包括艾滋病毒、结核病和疟疾。目前控制土壤传播线虫的全球规划主要依赖于使用驱虫药物的大规模给药（MDA），以减少或预防流行人群的发病率——预防性化疗。2007年，我们在加纳金坦波北市（Kintampo North Municipality， KNM）的社区开展了钩虫感染流行病学的试点研究，发现钩虫感染的高流行率（45%）与成年人营养状况不佳有关，在服用单剂量阿苯达唑（400mg）后，治疗失败率也很高（39%）。2010年的一项后续研究证实，学龄儿童中钩虫的患病率很高（39%），56%的阿苯达唑治疗失败。这些研究证实阿苯达唑在研究人群中的有效性有限，其机制仍有待阐明。在另一项初步研究中，我们对从同一地点分离的人钩虫中ß-微管蛋白基因作为潜在的苯并咪唑抗性标记进行了调查，并确定了作为潜在抗性标记的突变。这项拟议研究的具体目的将进一步确定钩虫感染的流行病学和与KNM中阿苯达唑治疗失败相关的特定宿主因素，并建立体外检测苯并咪唑耐药性和相应基因多态性的方法，用于加纳各地的哨点。我们预测，包括总体营养状况和特定饮食摄入在内的宿主因素会影响对阿苯达唑治疗的反应和对钩虫再次感染的易感，并且在治疗失败率和营养不良发生率高的社区中，遗传介导的钩虫对驱虫的抗性将出现。

DESCRIPTION (provided by applicant): Approximately one billion people are infected with hookworms (Necator americanus and Ancylostoma duodenal) which are a major global cause of anemia and malnutrition. Sub-Saharan Africa has the highest prevalence (29%) of global hookworm infection. Infections are responsible for sublime morbidity including impairment of both cognitive ability and growth observed in affected children. Vulnerable groups also include pregnant women. Evidence also suggests that chronic low intensity hookworm infection may impair the ability to control other tropical diseases, including HIV, tuberculosis, and malaria. Current global programs to control soil-transmitted nematodes rely primarily on mass drug administration (MDA) with anthelminthic drugs to either reduce or prevent morbidity - preventive chemotherapy - in endemic populations. We conducted pilot studies of the epidemiology of hookworm infection in communities in Kintampo North Municipality (KNM), Ghana in 2007 and found a high prevalence of hookworm infection (45%) that correlated with poor nutritional status in adults, as well as a high rate of treatment failure (39%) following administration of single dos albendazole (400mg). A follow-up study in 2010 confirmed the high prevalence of hookworm (39%) in school age children, and 56% albendazole treatment failure. These studies confirm the limited effectiveness of albendazole in the study population, the mechanisms of which remain to be elucidated. In another preliminary study we interrogated the ß-tubulin gene as a potential benzimidazole resistance marker in human hookworms isolated from the same sites and have identified mutations that are potential markers of resistance. The specific aims of this proposed research will further define the epidemiology of hookworm infection and the specific host factors associated with albendazole treatment failure in KNM and also establish methods to detect in vitro benzimidazole resistance and corresponding gene polymorphisms for use in sentinel sites throughout Ghana. We predict that host factors, including overall nutritional status and specific dietary intake influence response to albendazole therapy and susceptibility to re-infection with hookworm and that genetically mediated resistance of hookworms to anthelminthics will emerge in communities characterized by high coincident rates of treatment failure and malnutrition.