Determinants of resistance in human schistosomiasis

描述(由申请人提供)：曼氏血吸虫感染在非洲大部分地区仍然是一个主要的公共卫生问题，现在很明显，慢性血吸虫感染可能导致严重和轻微的发病率。后者被低估了，但可能对全球整体公共卫生产生更大的影响。我们和其他人有证据表明，对血吸虫再感染的抵抗力可以在吡喹酮治疗后产生，特别是当这涉及到多轮治疗和再次感染时。了解导致严重和微妙的发病率并导致抵抗再感染的免疫反应以及这些反应的免疫调节对于确定有效的大规模化疗计划以及超越大规模化疗作为唯一控制手段可能是重要的。虽然血吸虫病是一种公共卫生威胁，但它也会影响无关的免疫反应；例如，对当前疫苗的反应，以及在新候选疫苗的临床试验、合并感染、特应性过敏和自身免疫性疾病等情况下。这项建议的目的是：a)更好地了解与发病率和再感染抵抗力相关的潜在免疫调节和免疫反应；以及b)确定血吸虫病对血吸虫病母亲所生婴儿和在血吸虫病治疗前或治疗后免疫的成年人的标准免疫接种疫苗反应的影响。其具体目标是：1)血吸虫病中T调节细胞和Th17细胞的功能分析；2)用吡喹酮控制血吸虫病的标准年度大规模用药后儿童免疫反应改变的发展和发病率的分析；以及3)血吸虫病对受感染母亲所生儿童和成人中非血吸虫疫苗诱导的免疫反应的影响的建立和机制。每个具体目标都是基于从初步发现和有关血吸虫病人类免疫学的文献中产生的假设。这项研究将在肯尼亚基苏木及其附近的队列中进行，那里的维多利亚湖全年都有曼氏葡萄球菌的传播，这项研究基于14年的纵向合作研究。这些方法将主要是分析明确的临床和流行病学结果与免疫参数之间的关系，例如：用流式细胞仪进行外周血白细胞表型分析；通过全血培养对血吸虫和其他抗原的反应；然后对产生的细胞因子和血浆抗体水平进行多重分析。这些研究将产生与公共卫生相关的实际结果，例如蠕虫治疗后接种疫苗前所需的时间，以及可能优化的大规模药物管理控制计划，以减少感染相关的发病率。他们还将回答有关血吸虫病期间免疫调节以及血吸虫感染如何改变适应性免疫反应的基本免疫学问题。 与公共卫生相关：血吸虫病是一种使人衰弱的慢性蠕虫感染，在非洲大部分地区以及亚洲部分地区、中东和南美洲约有2亿人感染，影响儿童发育，可能导致危及生命的疾病，并可能干扰对针对其他感染的疫苗的反应能力，但只有一种有效药物，没有针对这种广泛传播的疾病的疫苗。这些免疫学研究将确定人们是否以及如何因药物吡喹酮的多重治疗而对再次感染产生更强的抵抗力，以及血吸虫病是否会阻碍婴儿和成年人对标准疫苗的良好反应能力，以及这种干扰是如何介导的。这些研究与当前推荐的治疗方案和未来的干预措施有关，以控制血吸虫病和其他疾病的全球公共卫生挑战，在这些疾病中，标准儿童或成人疫苗的效力可能会因血吸虫病而减弱。

DESCRIPTION (provided by applicant): Infection with Schistosoma mansoni remains a major public health problem in much of Africa, and it is now clear that chronic schistosome infections can lead to both severe and subtle morbidity. The latter is under- estimated, but likely has the greater impact on overall global public health. We and others have evidence that resistance to reinfection with schistosomes can develop after praziquantel treatment, especially when this involves multiple rounds of treatments and reinfections. Understanding the immune responses that cause severe and subtle morbidity and are responsible for resistance to reinfection and the immunoregulation of those responses may be important in determining effective scheduling of mass chemotherapy as well as moving beyond mass chemotherapy as the only means of control. While schistosomiasis is a public health threat, it can also impact unrelated immune responses; for example, to current vaccines and in situations like clinical trials of new candidate vaccines, co-infections, atopic allergies and autoimmune diseases. The objectives of this proposal are to: a) achieve a better understanding of the underlying immunoregulation and immune responses that correlate with both morbidity and resistance to reinfection; and b) determine the impact of schistosomiasis on standard Expanded Program of Immunization vaccine responses in infants born of mothers with schistosomiasis and adults immunized before or after treatment for their schistosomiasis. The Specific Aims are: 1) Functional analyses of T regulatory and Th17 cells in schistosomiasis; 2) Analyses of the development of altered immune responses and morbidity in children following standard annual mass drug administration with praziquantel for control of schistosomiasis; and 3) Establishment and mechanisms of the impact of schistosomiasis on non-schistosome related vaccine-induced immune responses in children born of infected mothers, and in adults. Each Specific Aim is based on hypotheses generated from preliminary findings and the literature on human immunology in schistosomiasis. The research will be done with cohorts in and near Kisumu, Kenya, where there is year-round transmission of S. mansoni in Lake Victoria, and is based on 14 years of collaborative, longitudinal studies. The methodologies will primarily be analyses of the relationships between well defined clinical and epidemiologic findings and such immune parameters as: peripheral blood leukocyte phenotyping by flow cytometry; responses to schistosome and other antigens by whole blood cultures followed by multiplex analyses of the cytokines produced, and plasma antibody levels. These studies will produce practical, public health-related findings, such as the time needed after helminth treatment before immunizations, and possible optimization of mass drug administration control programs to achieve reductions in infection-associated morbidity. They will also answer basic immunologic questions about immunoregulation during schistosomiasis and how schistosome infections alter adaptive immune responses. PUBLIC HEALTH RELEVANCE: Schistosomiasis is a debilitating, chronic worm infection of about 200 million people in much of Africa and parts of Asia, the Middle East and South America that impacts childhood development, can lead to life threatening disease, and can interfere with the ability to respond to vaccines against other infections, but there is only one effective drug and no vaccine for this widespread disease. These immunologic studies will determine if and how people become more resistant to reinfection due to multiple treatments with the drug praziquantel as well as see if schistosomiasis hampers the ability of infants and adults to respond well to standard vaccines and how this interference is mediated. These studies are relevant to both current recommended treatment programs and future interventions to control the global public health challenge of schistosomiasis and other diseases in which efficacy of standard childhood or adult vaccines may be damped due to schistosomiasis.