A RHESUS MONKEY MODEL OF MALARIA IN PREGNANCY

孕妇感染疟疾对胎儿和婴儿具有破坏性影响，导致流产、早产、宫内发育迟缓、发育不良、婴儿死亡和先天性感染。这项建议的长期目标是阐明妊娠期疟疾的发病机制，以便能够设计出有效的干预措施来预防这些并发症。具体目的是确定胎次和先前接触疟原虫对母亲、胎儿和新生儿临床疟疾的病程、严重程度和结局的影响，并验证巨噬细胞诱导的细胞因子失衡导致胎盘形态和生理性病变，从而导致胎儿损伤、出生后发育不良和先天性感染的假设。我们开发了一种动物模型，利用感染了革内疟原虫的怀孕恒河猴来研究这个问题。使用这个模型，将研究四组8只恒河猴。这些将是无产的原孕、次孕或多胎动物。这些猴子将在怀孕的前三个月被定时繁殖并接种革内疟原虫。分娩后，这些母亲将接受疟疾治疗。在第二年和第三年，这些动物将再次繁殖并重新接种疟原虫，每只动物和群体作为自己的对照。动物将没有免疫力，或者有过一两次接触疟原虫的经历。该设计将允许我们检查胎次和先前接触疟原虫对胎儿/婴儿结局的影响。婴儿将通过剖宫产分娩，以便从所有动物身上收集胎盘组织。胎盘将通过RT- PCR、免疫组织化学和原位杂交来检测细胞类型、细胞因子和生长因子，这些细胞类型、细胞因子和生长因子在胎盘发育和疟疾中很重要且可能相互作用。这些研究的结果将与胎盘切片的组织病理学、母亲的临床过程和新生儿的结局有关。这项设计将验证巨噬细胞及其产生的细胞因子可能是胎儿损伤的原因这一假设。从这些研究中获得的信息将有助于设计有效的干预措施，防止疟疾对孕妇及其子女的破坏性影响。

Malaria in pregnant women has devastating effects on the fetus and infant, resulting in abortions, premature deliveries, intrauterine growth retardation, failure to thrive, infant mortality and congenital infection. The long term objective of this proposal is to clarify the pathogenesis of malaria in pregnancy so that effective interventions that prevent these complications can be devised. The specific aims are to determine the effects of parity and prior exposure to Plasmodium on the course, severity, and outcome of clinical malaria in the mother, fetus, and newborn and to test the hypothesis that macrophage-induced cytokine imbalance causes morphologic and physiologic placental lesions that result in fetal damage, post-natal failure to thrive, and congenital infection. We have developed an animal model utilizing pregnant rhesus monkeys infected with Plasmodium coatneyi with which to study this problem. Using this model, four groups of eight rhesus monkeys will be studied. These will be nulliparous primagravida, secundigravida or multigravida animals. The monkeys will be time-bred and inoculated with Plasmodium coatneyi during the first trimester of pregnancy. After delivery, the mothers will be treated for malaria. In the second and third years, these same animals will be bred again and reinoculated with Plasmodium, with each animal and group serving as its own control. Animals will be non- immune, or have one or two previous exposures to Plasmodium. This design will allow us to examine the effects of parity and prior exposure to Plasmodium on fetal/infant outcome. Infants will be delivered by cesarean section so that placental tissues can be collected from all animals. The placentas will be examined by RT- PCR, immunohistochemistry, and in situ hybridization for cell types, cytokines, and growth factors that are important and likely to interact in placental development and malaria. The results of these studies will be correlated with histopathology of placental sections the clinical course in the mother, and the outcome of the newborn. This design will test the hypothesis that macrophages and the cytokines they produce are the likely causes of fetal injury. The information derived from these studies will allow effective interventions to be designed which will prevent the devastating effects of malaria in pregnant women and their children.