URINARY SCHISTOSOMIASIS: INFECTION AND DISEASE

这一建议源于15年来对S.在肯尼亚海岸省发生的一起埃及血吸虫感染事件中，这些事件对治疗、感染和发病率之间关系的传统概念提出了挑战。 对于鼠伤寒沙门氏治疗前的感染强度在人与人之间、家庭与家庭之间和村庄与村庄之间存在显著差异。 在肯尼亚接受治疗的人群中，我们的长期随访观察到学龄儿童感染强度降低，急性发病率降低，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以后的发病率，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、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ICIDR代表了对人类对疾病和发病率易感性变化的主要来源的系统评价。 由于疾病本身的特征与年龄有关，因此将从暴露前儿童、表现出早期疾病形式的儿童和表现出晚期疾病的成人中寻找因素。流行病学、人口统计学、寄生虫学和社会学因素将被量化和分析。 这些量化的风险因素将反过来用于分析表型的家族分离，以及遗传标记和易感性之间的联系。 将专门分析纳塔尔前暴露于溶酶体抗原和儿童期淋巴细胞中TNF α和TGF β产生的影响，以确定其对观察到的感染和结局变异性的贡献。 将在具体目标1中通过横断面和前瞻性研究评价流行病学因素，这些研究将评价和量化年龄、性别、文化和社会经济背景、感染强度和水接触的影响。这些研究将提供风险变量的估计值，用于特定目标2中的遗传学研究。 具体目标3将检查新生儿和婴儿产前暴露对学龄儿童结局和细胞因子TNF α和TGF β表达的影响。 这些信息，结合流行病学模型的控制策略，将允许加速合成下一代的控制程序。

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.