Fetal Immunity to Falciparum Malaria

描述(申请人提供)：在撒哈拉以南非洲，恶性疟疾导致的婴儿死亡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率发生在出生后的头两到三年内；此后由于对血液阶段感染获得免疫力，发病率有所下降。怀孕增加了部分免疫的妇女对疟疾的易感性，因此非洲婴儿通常是在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能会穿过胎盘，使胎儿暴露。这可能会导致胎儿免疫系统对潜在的保护性血液期抗原(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暴露于疟疾如何影响对血期感染的免疫力。一个直接的目标是表征胎儿T细胞(TC)对裂殖子表面蛋白-1(MSP-142)C末端42kD片段的反应，MSP-142是一种看起来很有希望作为疫苗候选抗原的疟疾抗原。我们试图阐明这种出生前的免疫经历如何影响出生到3岁之间获得对MSP-142的T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MSPl42特异性记忆TC的产生，以及针对MSP1 C末端部分的更高抗体水平，从而抑制婴儿时期的红细胞入侵。相反，胎儿对疟疾的光照暴露会产生相反的效果，形成TC无能或产生T调节细胞，导致MSP-142特异性T辅助细胞频率降低，侵袭抑制抗体水平降低，从而增加疟疾感染的风险。 这些假设将在以下特定目标中进行评估：(1)确定在疟疾流行人群中从新生儿子宫中获得的疟疾特异性T细胞的表型和频率。(2)明确胎儿暴露于MSP142的机制及其对宫内获得的恶性T细胞表型的调节作用。(3)探讨宫内获得的MSP142特异性CD45RA记忆细胞的类型是否影响MSP1特异性T细胞的频率和表型，以及从出生到3岁的MSP119的侵袭抑制抗体水平。

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.