Pregnancy-Associated Horomones and Immune to Malaria

描述(申请人提供)：孕妇比非孕妇更容易感染恶性疟原虫。导致他们易感性增加的机制尚不清楚，但与怀孕相关的激素被认为是重要的，因为它们下调了先天性和获得性免疫反应。关于哪种激素(S)负责、特异性抗疟免疫反应(S)改变的性质或它们如何影响疟疾易感性的信息很少。其中一个主要的 孕期恶性疟的后果是早产(PTD)风险增加。早产婴儿在出生后的第一年有很大的死亡风险。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他们提前分娩。寄生虫改变导致PTD的事件顺序的机制尚未被研究。在考虑了在疟疾免疫中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类绒毛膜促性腺激素、皮质醇和催乳素如何相互作用来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，说明疟疾寄生虫如何上调合体滋养层细胞的促肾上腺皮质激素释放激素，并启动导致PTD的事件。这只是众多可以提出的模式中的两个，具有很高的探索性。因此，R21应用的主要目的是通过我们对喀麦隆怀孕妇女的持续研究，使用已经收集的临床数据和样本，进行关键实验，以帮助测试这些模型。如果任何一个模型被证明是正确的，它将打开新的研究途径的大门，帮助识别怀孕期间重要的抗疟疾免疫反应，并可能为识别患有疟疾相关PTD风险的妇女提供诊断标记物。

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.