Schistosoma Mansoni Infection During Pregnancy: Dissecting the Implications to Fetal Immunity

母体蠕虫感染与危重新生儿和新生儿的疗效降低有关 儿童免疫接种。约4000万育龄妇女面临感染血吸虫病的风险 在非洲，至少有1000万妇女在怀孕期间感染了血吸虫病，但人们对这种疾病知之甚少 产前暴露对子代免疫反应的影响。来自先前研究的发现 这表明胎儿在子宫内可能接触到蠕虫抗原，因此日本血吸虫病的高发 这一人群代表着一个重大的潜在公共卫生问题。世界卫生组织最近建议 对所有蠕虫检测呈阳性的孕妇进行驱虫治疗；然而，很少有研究发现 评估药物治疗对母亲或胎儿的免疫学影响。驱虫剂 治疗和由此产生的寄生虫抗原的释放有可能在很大程度上使胎儿过敏 就像自然感染一样。考虑到潜在的严重的不利病理和免疫学 关于母体感染和驱虫治疗的后果，我们必须了解 产前蠕虫感染的免疫学后果，以便提出适当的建议 旨在解决当前实践中的任何问题，并最终帮助改善免疫反应 资源贫乏国家的婴儿。我们在这个提案中的目标是确定免疫学上的 (S)产前感染曼氏血吸虫调节动态平衡免疫环境的机制， 以及这种免疫调节对小鼠对抗原攻击的出生后免疫反应的影响 母体感染曼氏沙门氏菌模型。我们的中心假设是在子宫内暴露于曼氏葡萄球菌 抗原降低共刺激分子CD21/35的稳态表达，并前提 发育中胎儿的淋巴结致出生后Th2偏斜的免疫反应减弱 用免疫无关的抗原进行免疫。我们提出了三个具体目标来测试这一点：1)定义 小鼠出生前暴露于曼氏血吸虫感染对出生后外周血的调节机制(S) 淋巴结动态平衡；2)定义产前暴露于曼氏葡萄球菌感染的机制(S) 调节出生后对无关抗原挑战的细胞免疫反应；3)确定 孕鼠驱虫治疗对仔鼠出生后疫苗免疫的影响 后代。在这些研究完成后，我们预计已经确定了关键的免疫机制， 感染曼氏葡萄球菌的母亲所生子女的免疫力下降是其原因。很可能这些机制 将包括抗原提呈能力降低以及抗原提呈细胞和T细胞的预适应 引导Th2反应；然而，即使它不是，我们也希望有确定的关键 免疫力下降的机制。成功完成这些研究可望有一个 对感染蠕虫的孕妇的治疗策略未来可能产生重要的积极影响。

Maternal helminth infections have been implicated in the reduced efficacy of critical life-saving neonatal and childhood immunizations. Approximately 40 million women of childbearing age are at risk for schistosomiasis and at least 10 million women in Africa have schistosomiasis during pregnancy, yet little is known about the impact of prenatal exposure on the immune responsiveness of offspring. Findings from previous studies indicate that a fetus can be exposed to helminth antigens in utero, so the high frequency of schistosomiasis in this population represents a significant potential public health problem. The WHO recently recommended anthelminthic treatments for all pregnant women who test helminth positive; however, very few studies have evaluated the immunological impact of drug treatment on either the mother or the fetus. Anthelminthic treatment and the resultant release of parasite antigens have the potential to sensitize a fetus in much the same way that natural infection does. Given the potentially serious adverse pathological and immunological consequences of both maternal infection and anthelminthic treatment, it is critical that we understand the immunological consequences of prenatal helminth infection, so that appropriate recommendations can be formulated to address any issues with current practices and, ultimately, help to improve immune responses in infants in resource-poor countries. Our objective in this proposal is to determine the immunological mechanism(s) through which prenatal S. mansoni infection modulates the homeostatic immune environment, and the effect this immune-modulation has on post-natal immune responses to antigenic challenge in a mouse model of maternal S. mansoni infection. Our central hypothesis is that in utero exposure to S. mansoni antigens reduces the steady-state expression of the co-stimulatory molecules CD21/35, and preconditions lymph nodes in the developing fetus towards a muted Th2-skewed immune response following postnatal immunization with immunologically unrelated antigens. We propose three specific aims to test this: 1) Define the mechanism(s) by which prenatal exposure of mice to S. mansoni infection modulates postnatal peripheral lymph node homeostasis; 2) Define the mechanism(s) by which prenatal exposure to S. mansoni infection modulates postnatal cellular immune responses to unrelated antigenic challenge; 3) Determine the consequences of anthelminthic treatment of infected pregnant mice on postnatal vaccine-induced immunity of offspring. At the completion of these studies, we expect to have identified key immunological mechanisms that underlie reduced immunity in offspring born to mothers infected with S. mansoni. It is likely these mechanisms will include reduced antigen presentation ability and preconditioning of antigen presenting cells and the T cell compartment towards priming a Th2 response; however even if it is not, we expect to have identified key mechanisms underlying reduced immunity. Successful completion of these studies can be expected to have a potentially important future positive impact on strategies for treatment of helminth-infected pregnant women.