Fetal Immunity to Falciparum Malaria

描述（由申请人提供）：恶性疟原虫疟疾在撒哈拉以南非洲造成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，与疟疾有关的大部分发病发生在出生后的头两三年内;此后由于获得了对血液阶段感染的免疫力，发病率下降。怀孕增加了部分免疫妇女对疟疾的易感性，因此非洲婴儿往往是由怀孕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穿过胎盘并暴露于胎儿。这可能导致胎儿免疫系统变得敏感，或者对潜在的保护性血液阶段抗原（如参与红细胞入侵的裂殖子表面蛋白）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。一个直接的目标是表征胎儿T细胞（Tc）的记忆反应裂殖子表面蛋白-1（MSP-142），疟疾抗原，看起来有希望作为疫苗候选抗原的C-末端42 kD片段。我们试图澄清这种产前免疫经验如何影响出生至3岁之间获得对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MSP 142特异性记忆Tc的产生，以及对MSP 1的C末端部分的较高抗体水平，从而抑制婴儿期红细胞侵袭。相反，胎儿暴露于疟疾的光将通过Tc无反应性的发展或T调节细胞的产生相反的效果，导致MSP-142特异性T辅助细胞的频率降低和侵袭抑制性Ab的水平降低，从而增加疟疾感染的风险。 这些假设将在以下具体目标中进行评估：（1）确定疟疾流行人群中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CD 45 RA记忆细胞的类型是否影响出生至3岁期间MSP 1特异性T细胞的频率和表型以及MSP 119的侵袭抑制性Ab的水平。

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.