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

怀孕期间曼氏血吸虫感染：剖析对胎儿免疫的影响

• 批准号: 10331295
• 负责人: Keke Celeste Fairfax
• 金额: $ 46.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331295
• 关键词: Address; Africa; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated; B-Lymphocytes; BCG Live; Cell Compartmentation; Childhood; Chronic; Communicable Diseases; Complement 3d Receptors; Country; Development; Diagnosis; Diphtheria; Environment; Exposure to; Family; Female of child bearing age; Fetal Development; Fetus; Frequencies; Future; Generations; Goals; Health Professional; Helminth Antigens; Helminths; Hepatitis B; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; Infant; Infection; Interleukin-4; Life; Memory; Memory B-Lymphocyte; Modeling; Mothers; Mus; Neonatal; Outcome; Parasites; Parasitic infection; Pathologic; Peripheral; Pharmacotherapy; Platyhelminths; Play; Population; Positioning Attribute; Praziquantel; Pregnancy; Pregnant Women; Public Health; Recommendation; Reporting; Research; Research Personnel; Resources; Risk; Role; Savings; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Schistosomiasis; Signal Transduction; Stromal Cells; Structure of germinal center of lymph node; T-Lymphocyte; TNF gene; Testing; Tetanus; Th2 Cells; Tuberculosis; Vaccines; Woman; early childhood; fetal immunity; helminth infection; immunogenic; immunoregulation; improved; in utero; lymph nodes; mouse model; neglected tropical diseases; offspring; postnatal; preconditioning; pregnant; prenatal; prenatal exposure; response; treatment strategy; vaccine efficacy; vaccine-induced immunity

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.

母体蠕虫感染与关键的新生儿救生药物的疗效降低有关， 儿童免疫。约有4000万育龄妇女面临血吸虫病风险 非洲至少有1000万妇女在怀孕期间患有血吸虫病，但人们对血吸虫病的发病机制知之甚少。 产前暴露对后代免疫反应的影响。以往研究的结果 表明胎儿在子宫内就可以接触到蠕虫抗原，因此， 这一人群是一个重大的潜在公共卫生问题。世卫组织最近建议， 驱虫治疗的所有孕妇谁测试蠕虫阳性;然而，很少有研究， 评估药物治疗对母亲或胎儿的免疫影响。驱虫 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致敏胎儿， 就像自然感染一样考虑到潜在的严重不良病理学和免疫学反应， 由于产妇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后果，以便适当的建议， 制定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。我们的目标是确定免疫学 机制（S）通过产前S。曼氏感染调节稳态免疫环境， 以及这种免疫调节对小鼠出生后对抗原攻击的免疫应答的影响 母本S.曼氏感染。我们的中心假设是子宫内暴露于S。曼氏 抗原降低共刺激分子CD 21/35的稳态表达， 淋巴结在发育中的胎儿走向沉默的Th 2偏态免疫反应后出生 用免疫学上不相关的抗原进行免疫。我们提出了三个具体的目标来测试这一点：1）定义 小鼠产前暴露于S.曼氏感染调节出生后外周血 淋巴结内稳态; 2）定义产前暴露于S.曼氏感染 调节出生后对无关抗原攻击的细胞免疫应答; 3）确定 驱虫治疗感染的孕鼠对产后疫苗诱导的免疫力的影响 后代在这些研究完成后，我们希望已经确定了关键的免疫机制， 是感染沙门氏菌母亲所生后代免疫力下降的基础。mansoni很可能这些机制 将包括抗原呈递能力降低和抗原呈递细胞和T细胞的预处理 然而，即使不是这样，我们也希望已经确定了关键的 免疫力下降的潜在机制。成功完成这些研究可以预期有一个 这对今后治疗感染蠕虫的孕妇的战略可能产生重要的积极影响。