Plasmodium falciparum malaria elicits inflammatory responses that dysregulate placental amino acid transport.
Plasmodium falciparum malaria elicits inflammatory responses that dysregulate placental amino acid transport.
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DOI：
10.1371/journal.ppat.1003153
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发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Rogerson SJ
中科院分区：
文献类型：
--
作者：
Boeuf P;Aitken EH;Chandrasiri U;Chua CL;McInerney B;McQuade L;Duffy M;Molyneux M;Brown G;Glazier J;Rogerson SJ
胎盘性疟疾(PM)可导致不良的新生儿结局，包括因胎儿生长受限(FGR)而导致的低出生体重，特别是当与局部炎症(绒毛膜炎或IV)相关时。PM相关性FGR的发病机制尚不清楚，但在特发性FGR中，已发现胎盘氨基酸转运受损，尤其是通过A组氨基酸转运蛋白系统。我们推测PM相关的FGR可能是静脉注射引起的经胎盘氨基酸转运障碍所致。在马拉维妇女及其婴儿的队列中，PM患者A系统的表达和活性(通过Na+依赖的14C-MeAIB摄取测量)与未感染的胎盘相比降低，尤其是与静脉注射相关的胎盘。在PM合并IV的体外模型中，胎盘细胞暴露于单核细胞/感染的红细胞条件培养液中，显示A系统活性降低。用反相超高效液相色谱分析母体和脐带血浆中氨基酸的浓度，发现胎盘对氨基酸的转运发生了特殊的变化，尤其是静脉注射。总体而言，我们的数据表明胎儿胎盘单位通过改变胎盘氨基酸的转运来维持足够的胎儿生长。然而，IV更深刻地损害了胎盘氨基酸的运输功能，导致FGR。我们的研究首次为PM中FGR的发病机制提供了解释孕期感染疟疾可导致胎儿生长受限和低出生体重，并伴随高婴儿死亡率和发病率。胎盘性疟疾胎儿生长受限的发病机制尚不清楚，但在其他病理性妊娠中，已发现胎盘氨基酸转运受损。在一组马拉维妇女和她们的婴儿中，我们发现胎盘性疟疾，特别是当与局部炎症有关时，与一组重要的氨基酸胎盘转运蛋白的表达和活性降低有关。使用胎盘疟疾局部炎症的体外模型，我们发现母体单核细胞产品可以损害胎盘细胞上氨基酸转运体的活性。配对的母体和脐带血浆中的氨基酸浓度揭示了胎盘疟疾对氨基酸运输的特殊改变，特别是伴随局部炎症。总体而言，我们的数据表明，除了疟疾感染本身，它引发的局部炎症还会损害胎盘氨基酸运输功能，导致胎儿生长受限。在疟疾和产妇营养不良并存威胁数百万婴儿健康和生命的世界地区，加强对所涉机制的了解，并采取干预措施改善疟疾中的胎儿发育，是重要的优先事项。
Placental malaria (PM) can lead to poor neonatal outcomes, including low birthweight due to fetal growth restriction (FGR), especially when associated with local inflammation (intervillositis or IV). The pathogenesis of PM-associated FGR is largely unknown, but in idiopathic FGR, impaired transplacental amino acid transport, especially through the system A group of amino acid transporters, has been implicated. We hypothesized that PM-associated FGR could result from impairment of transplacental amino acid transport triggered by IV. In a cohort of Malawian women and their infants, the expression and activity of system A (measured by Na+-dependent 14C-MeAIB uptake) were reduced in PM, especially when associated with IV, compared to uninfected placentas. In an in vitro model of PM with IV, placental cells exposed to monocyte/infected erythrocytes conditioned medium showed decreased system A activity. Amino acid concentrations analyzed by reversed phase ultra performance liquid chromatography in paired maternal and cord plasmas revealed specific alterations of amino acid transport by PM, especially with IV. Overall, our data suggest that the fetoplacental unit responds to PM by altering its placental amino acid transport to maintain adequate fetal growth. However, IV more profoundly compromises placental amino acid transport function, leading to FGR. Our study offers the first pathogenetic explanation for FGR in PM. Malaria infection during pregnancy can cause fetal growth restriction and low birthweight associated with high infant mortality and morbidity rates. The pathogenesis of fetal growth restriction in placental malaria is largely unknown, but in other pathological pregnancies, impaired transplacental amino acid transport has been implicated. In a cohort of Malawian women and their infants, we found that placental malaria, especially when associated with local inflammation, was associated with decreased expression and activity of an important group of amino acid placental transporters. Using an in vitro model of placental malaria with local inflammation, we discovered that maternal monocyte products could impair the activity of amino acid transporters on placental cells. Amino acid concentrations in paired maternal and cord plasmas revealed specific alterations of amino acid transport by placental malaria, especially with local inflammation. Overall, our data suggest that, more than malaria infection per se, the local inflammation it triggers compromises placental amino acid transport function, leading to fetal growth restriction. Greater understanding of the mechanisms involved, combined with interventions to improve fetal growth in malaria, are important priorities in areas of the world where the co-existence of malaria and maternal malnutrition threatens the health and lives of millions of young babies.
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影响因子：
3
作者：
Ayoola OO;Whatmore A;Balogun WO;Jarrett OO;Cruickshank JK;Clayton PE
通讯作者：
Clayton PE
DOI：
10.2741/s162
发表时间：
2011-01-01
期刊：
Frontiers in bioscience (Scholar edition)
影响因子：
--
作者：
Brown LD;Green AS;Limesand SW;Rozance PJ
通讯作者：
Rozance PJ
影响因子：
4.4
作者：
Abrams, ET;Brown, H;Rogerson, SJ
通讯作者：
Rogerson, SJ
影响因子：
105.7
作者：
Ceesay, SM;Prentice, AM;Whitehead, RG
通讯作者：
Whitehead, RG
影响因子：
6.3
作者：
CHIEN, PFW
通讯作者：
CHIEN, PFW