URINARY SCHISTOSOMIASIS: INFECTION AND DISEASE

这一建议源于对肯尼亚海岸省15年血吸虫感染的研究，这些研究挑战了治疗、感染和发病率之间关系的传统概念。对于血瘤沙门氏菌以及其他蠕虫感染，治疗前的感染强度显示出明显的人与人、家庭与家庭和村庄与村庄之间的差异。在肯尼亚接受治疗的人群中，我们的长期随访期使我们能够观察到学龄儿童感染强度和急性发病率的减少，但许多人在成年后出现肾积水。因此，对于早期感染和疾病以及生命后期的发病率，寄生虫暴露的差异不能充分解释蠕虫负担和疾病结局的异质性。越来越多的证据表明，感染和疾病的聚集分布在很大程度上是由于环境因素的差异、基于人类生物学的遗传差异或某些宿主的特定免疫机制。这一单一项目的ICIDR代表了对人类疾病易感性和发病率变化的主要来源的系统评估。由于疾病本身的特征与年龄有关，因此将从预先接触过的儿童、表现出早期疾病形式的儿童和患有晚期疾病的成年人中寻找因素。流行病学、人口学、寄生虫学和社会学因素将被量化并分析关联。这些量化的风险因素将反过来被用来分析表型的家族隔离，以及遗传标记和易感性之间的联系。将具体分析出生前暴露于血吸虫抗原和儿童时期淋巴细胞产生的肿瘤坏死因子α和转化生长因子β的影响，以确定它们对观察到的感染和结局的变异性的贡献。流行病学因素将在具体目标1中通过横断面和前瞻性研究进行评估，评估和量化年龄、性别、文化和社会经济背景、感染强度和接触水的影响。这些研究将提供将用于特定目标2的遗传学研究的风险变量的估计。特定目标3将检查新生儿和婴儿产前暴露对结果的影响以及学龄儿童细胞因子TNFpha和TGFbeta的表达。这些信息与控制策略的流行病学建模相结合，将使下一代控制计划的合成速度加快。

This proposal stems from 15 years of research on S. haematobium infection in Coast Province, Kenya that have served to challenge the traditional concept of the relationship among treatment, infection and morbidity. For S. haematobium, as well as other helminth infections, infection intensity before treatment shows significant person-to person, family-to-family and village-to- village variation. In treated populations in Kenya, our long follow-up period has permitted observation of reduced infection intensity and reduced acute morbidity among schoolchildren, but the development of hydronephrosis among many in adulthood. Thus, for early infection and disease as well as morbidity later in life, the heterogeneity of worm burden and disease outcome is not adequately explained by differences in parasite exposure. Increasing evidence suggests that the aggregated distributions of infection and disease is due in significant part to differences in environmental factors, genetically based differences in human biology or by specific immunologic mechanisms in some hosts. This single-project ICIDR represents a systematic evaluation of the major sources for variation in human susceptibility to disease and morbidity. Since characteristics of the disease itself are age dependent, factors will be sought from pre-exposed children, children demonstrating early forms of disease and adults presenting with late disease will be specifically targeted. Epidemiologic, demographic, parasitologic and sociologic factors will be quantified and analyzed for associations. These quantified risk factors will in turn be used to analyze familial segregation of phenotypes, as well as linkage between genetic markers and susceptibility. The effect of pre- natal exposure to schistosome antigens and childhood TNFalpha and TGFbeta production in lymphocytes will be specifically analyzed for their contribution to the observed variability in infection and outcome. Epidemiologic factors will be evaluated in Specific Aim 1 by cross-sectional and prospective studies that will evaluate and quantify the impact of age, sex, cultural and socio- economic background, intensity of infection and water contact. These studies will provide estimates of risk variables that will be used for genetic studies in Specific Aim 2. Specific Aim 3 will examine neonates and infants for the effect of prenatal exposure on outcome and the expression of the cytokines TNFalpha and TGFbeta in school-aged children. This information, combined with epidemiological modeling of control strategies, will allow accelerated synthesis of the next generation of control programs.