Pregnancy-Associated Hormones and Immune to Malaria

描述（由申请人提供）：孕妇比非孕妇更有可能感染恶性疟原虫。其易感性增加的机制尚不清楚，但妊娠相关激素被认为是重要的，因为它们下调先天和获得性免疫反应。关于哪种激素起作用、特异性抗疟免疫反应的性质改变或它们如何影响疟疾易感性的信息很少。的一个主要 妊娠期间感染恶性疟原虫疟疾的后果是早产风险增加。早产儿在出生后第一年内死亡的风险很大。由于妊娠相关激素在控制分娩时间方面起着关键作用，恶性疟原虫直接或间接地刺激它们过早地开始分娩。寄生虫改变导致PTD的事件顺序的机制尚未研究。在考虑了对疟疾免疫至关重要的免疫反应以及特定激素如何下调它们之后，我们开发了一个假设模型来解释人绒毛膜促性腺激素，皮质醇和催乳素如何相互作用以抑制导致疟疾易感性的免疫反应。我们还开发了一个理论模型，疟疾寄生虫可以上调促肾上腺皮质激素释放激素从合体滋养细胞和启动事件导致PTD。这只是可以提出的众多模型中的两个，具有高度的探索性。因此，这项R21应用的主要目的是使用我们正在进行的对怀孕的爱沙尼亚妇女的研究中收集的临床数据和标本，进行有助于测试这些模型的关键实验。如果任何一种模型被证明是正确的，它将为新的研究途径打开大门，帮助识别在怀孕期间重要的抗疟疾免疫反应，并可能为识别有疟疾相关PTD风险的妇女提供诊断标志物。

DESCRIPTION (provided by the applicant): Pregnant women are more likely to become infected with Plasmodium falciparum than non-pregnant women. The mechanism responsible for their increased susceptibility is unknown, but pregnancy-associated hormones are considered to be important because they down-regulate innate and acquired immune responses. Little information is available on which hormone(s) are responsible, the nature of the specific antimalarial immune response(s) altered, or how they influence susceptibility to malaria. One of the major consequences of P. falciparum malaria during pregnancy is an increased risk of preterm deliveries (PTD). Infants born prematurely are at a significant risk of dying during their first year of life. Since pregnancy associated hormones play a key role in controlling the timing of parturition, P. falciparum parasites either directly or indirectly stimulate them to initiate labor prematurely. Mechanisms by which parasites alter the sequence of events leading to PTD have not been studied. After considering immune responses that are important in immunity to malaria and how specific hormones might down-regulate them, we developed a hypothetical model to explain how human chorionic gonadotropin, cortisol and prolactin might interact to suppress immune responses that result in susceptibility to malaria. We also developed a theoretical model on how malarial parasites could up-regulate corticotrophin-releasing hormone from syncytiotrophoblasts and initiate events leading to PTD. These are only two of numerous models that could be proposed and are highly exploratory. Thus, the primary aim of this R21 application is to use clinical data and specimens already collected, through our on-going research in pregnant Cameroonian women, in key experiments that will help test these models. If either model proves to be correct, it would open the door to new avenues of research, help identify antimalarial immune responses that are important during pregnancy, and possibly provide diagnostic markers for identifying women who are at risk of malaria-associated PTD.