Inflammation, Anemia and Respiratory Distress in Mothers and Infants with Malaria

描述(由申请人提供)：在非洲，每年有多达2000万孕妇接受抗疟疾药磺胺多辛(SP)的间歇性推定治疗(IPTp)，以防止恶性疟原虫感染胎盘；然而，没有人研究过对她们后代的长期影响。IPTp已被证明可以减少胎盘疟疾、严重孕产妇贫血、早产的发病率，并增加平均出生体重，特别是在妇女最易受影响的第一次和第二次怀孕期间。我们的初步研究表明，IPTp在胎盘感染中选择耐药等位基因，这些耐药等位基因与胎盘炎症和低出生体重的风险增加有关。此外，我们发现IPTp与在婴儿期感染后代的寄生虫中耐药等位基因的增加有关，并且在子宫中暴露于IPTp的婴儿在更小的年龄和更频繁的整个婴儿期经历寄生虫血症。该项目将研究我们观察到的这些新现象背后的机制，并扩展这些机制，以更好地了解IPTp对长期疾病结果的影响。在母亲中，我们将评估与抗药性寄生虫相关的炎症是否也影响母亲贫血的风险，特别是通过增加IL-6和海普西丁的水平。在儿童中，我们将研究IPTp是否不仅会增加寄生虫血症的风险，还会增加严重综合征的风险，包括严重贫血和呼吸窘迫。我们提出了IPTp可能导致疾病风险增加的三种替代机制：耐药寄生虫持续时间更长，导致更严重的临床疾病；耐药寄生虫增加炎症，这与严重疟疾综合征相关；耐药寄生虫毒力更强，并生长到更高的密度，这一现象被称为竞争促进，这可能导致临床疾病增加。我们将使用来自坦桑尼亚Muheza的孕妇及其后代的预期分娩队列的数据和样本来检验这些潜在的关系，这些孕妇及其后代在分娩后接受了长达三年的跟踪(2003-2006年)。我们有一个临床数据库，记录了妇女和婴儿的贫血和呼吸窘迫，我们将使用寄生虫基因分型将这些数据与感染持续时间联系起来，使用细胞因子和海普西丁测量炎症，以及寄生虫密度。公共卫生相关性：我们观察到，IPTp增加了后代的疟疾风险，这为更好地理解贫血和呼吸窘迫风险的可能机制创造了机会，这两种疾病是该人群的两大杀手。我们建议的研究对影响数千万孕妇的抗疟疾政策具有重要意义。

DESCRIPTION (provided by applicant): Up to 20 million pregnant women in Africa receive intermittent presumptive treatment (IPTp) with the antimalarial sulfadoxine-pyrimethamine (SP) each year to prevent P. falciparum infection of the placenta; however, no one has studied the long term effects on their offspring. IPTp has been shown to reduce the incidence of placental malaria, severe maternal anemia, pre-term delivery, and increase mean birth weight, particularly during first and second pregnancy when women are most susceptible. Our preliminary studies indicate that IPTp selects for drug resistance alleles in placental infections, and that these resistance alleles are associated with increased risk of placental inflammation and low birth weight. Further, we find that IPTp is associated with an increased abundance of resistance alleles in the parasites infecting the offspring during infancy, and that infants exposed to IPTp in utero experience parasitemia at a younger age and more frequently throughout infancy. This project will examine the mechanisms that underlie these novel phenomena we have observed, and extend these to better understand the effects of IPTp on long term disease outcomes. In the mothers, we will assess whether inflammation related to resistant parasites also affects risk of maternal anemia, specifically by increasing IL-6 and hepcidin levels. In the children, we will examine whether IPTp increases risk of not only parasitemia, but also the risk of severe syndromes, including severe anemia and respiratory distress. We propose three alternative mechanisms by which IPTp might contribute to increased risk of disease: resistant parasites persist for a longer duration, leading to more severe clinical disease; resistant parasites increase inflammation, which is associated with severe malaria syndromes; resistant parasites are more virulent and grow to a higher density, a phenomenon known as competitive facilitation, which may result in increased clinical disease. We will examine these potential relationships using data and samples from a prospective delivery cohort of pregnant women and their offspring from Muheza, Tanzania who were followed for up to three years after delivery (2003-2006). We have a clinical database recording anemia and respiratory distress in women and infants, and we will relate this data to duration of infection using parasite genotyping, inflammation using cytokine and hepcidin measures, and parasite density. PUBLIC HEALTH RELEVANCE: Our observation that IPTp increases malaria risk in offspring creates an opportunity to better understand the mechanisms that may underlie risk of anemia and respiratory distress, two major killers in this population. Our proposed studies have important relevance for antimalarial policy affecting tens of millions of pregnant women.