Fetal Immunity to Falciparum Malaria

胎儿对恶性疟疾的免疫力

• 批准号: 7218679
• 负责人: Christopher L King
• 金额: $ 36.62万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218679
• 关键词: Affect; Africa South of the Sahara; African; Age-Months; Age-Years; Antibodies; Antigens; Area; B-Lymphocytes; Birth; Blood; C-terminal; CD4 Positive T Lymphocytes; Cells; Clinical; Clinical Trials; Clonal Anergy; Cotyledon plant; Development; End Point; Erythrocytes; Exposure to; Falciparum Malaria; Fetus; Frequencies; Future; Generations; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Immune system; Immunity; Immunologics; Infant; Infant Mortality; Infection; Light; Lymphocyte; Malaria; Memory; Merozoite Surface Protein 1; Morbidity - disease rate; Mothers; Newborn Infant; Parasites; Perinatal Exposure; Phenotype; Placenta; Population; Predisposition; Pregnancy; Production; Reaction; Reporting; Risk; Staging; Structure of placental cotyledon; T memory cell; T-Cell Development; T-Lymphocyte; Time; Umbilical Cord Blood; Vaccines; Woman; anergy; base; ex vivo perfusion; experience; fetal; in utero; infancy; merozoite surface protein; prenatal; prenatal exposure; response; transmission process

DESCRIPTION (provided by applicant): Plasmodium falciparum malaria causes more infant mortality and morbidity in sub-Saharan Africa than any other single infection. In areas where malaria transmission is stable over time, the bulk of malaria-related morbidity occurs within the first two to three years after birth; it declines thereafter as a consequence of acquisition of immunity to blood-stage infection. Pregnancy increases the susceptibility of partially immune women to malaria, such that African infants are often born of mothers infected with malaria during gestation. Thus infected red blood cells, soluble antigenic products, or maternal lymphocytes and antibodies may cross the placenta and expose the fetus. This could result in the fetal immune system becoming sensitized, or alternatively tolerant, to potentially protective blood-stage antigens (such as merozoite surface proteins involved in invasion of red blood cells). Our overall goal is to examine how prenatal exposure to malaria influences immunity to blood-stage infection. An immediate objective is to characterize fetal T cell (Tc) memory in reaction to the C-terminal 42 kD fragment of Merozoite Surface Protein-1 (MSP-142), a malaria antigen that looks promising as a vaccine candidate antigen. We seek to clarify how this pre-natal immunologic experience impacts upon the acquisition of T- and B-cell immunity to MSP-142 between birth and 3 years of age. Our central hypothesis is that heavy exposure of the fetus to malaria antigens will stimulate production of MSPl42-specific memory Tc in utero, as well as higher antibodies levels to the C-terminal portion of MSP 1, thereby inhibiting red cell invasion during infancy. Conversely, light exposure of the fetus to malaria will produce the opposite effect by development of Tc anergy or generation of T regulatory cells, resulting in reduced frequency of MSP-142-specific T helper cells and lower levels of invasion inhibitory Abs, consequently increasing the risk for malaria infection. These hypotheses will be evaluated in the following specific aims: (1) To determine the phenotype and frequency of malaria-specific T cells acquired in utero from newborns in a malaria endemic population. (2) To define the mechanisms of fetal exposure to MSP 142 and how this exposure regulates the phenotypes of malariaspecific T cells acquired in utero. (3) To evaluate whether the type of MSP 142-specific CD45RA- memory cells acquired in utero affects the frequencies and phenotype of MSP 1-specific T cells and levels of invasion inhibitory Abs to MSP 119 from birth to 3 years of age.

描述（由申请人提供）：在撒哈拉以南非洲地区，恶性疟原虫疟疾导致的婴儿死亡率和发病率高于任何其他单一感染。在疟疾传播长期稳定的地区，大部分与疟疾相关的发病发生在出生后的头两到三年内；此后，由于获得了对血液阶段感染的免疫力，它会下降。怀孕会增加部分免疫的妇女对疟疾的易感性，因此非洲婴儿往往是由在妊娠期间感染疟疾的母亲所生。因此，受感染的红细胞、可溶性抗原产物或母体淋巴细胞和抗体可能穿过胎盘并暴露胎儿。这可能导致胎儿免疫系统对潜在的保护性血液阶段抗原（例如参与红细胞入侵的裂殖子表面蛋白）变得敏感或耐受。 我们的总体目标是研究产前接触疟疾如何影响对血液阶段感染的免疫力。近期目标是表征胎儿 T 细胞 (Tc) 记忆对裂殖子表面蛋白 1 (MSP-142) C 端 42 kD 片段的反应，裂殖子表面蛋白 1 (MSP-142) 是一种疟疾抗原，看起来很有希望成为疫苗候选抗原。我们试图阐明这种产前免疫经历如何影响出生至 3 岁时获得 MSP-142 的 T 细胞和 B 细胞免疫。我们的中心假设是，胎儿大量暴露于疟疾抗原将刺激子宫内MSP142特异性记忆Tc的产生，以及MSP1C末端部分的更高抗体水平，从而抑制婴儿期红细胞侵袭。相反，胎儿接触疟疾的光会产生相反的效果，产生Tc无反应性或产生T调节细胞，导致MSP-142特异性T辅助细胞的频率减少和侵袭抑制抗体水平降低，从而增加感染疟疾的风险。 这些假设将根据以下具体目标进行评估：（1）确定从疟疾流行人群的新生儿子宫内获得的疟疾特异性T细胞的表型和频率。 (2) 明确胎儿暴露于 MSP 142 的机制以及这种暴露如何调节子宫内获得的疟疾特异性 T 细胞的表型。 (3)评估子宫内获得的MSP 142特异性CD45RA记忆细胞的类型是否影响出生至3岁时MSP 1特异性T细胞的频率和表型以及针对MSP 119的侵袭抑制抗体的水平。