Cramer Jakob P, Nüssler Andreas K, Ehrhardt Stephan, Burkhardt Jana, Otchwemah Rowland N, Zanger Philipp, Dietz Ekkehart, Gellert Sabine, Bienzle Ulrich, Mockenhaupt Frank P
Institute of Tropical Medicine Berlin, Charité- University Medicine Berlin, Germany.
Trop Med Int Health. 2005 Jul;10(7):672-80. doi: 10.1111/j.1365-3156.2005.01438.x.
Nitric oxide (NO) has toxic properties against Plasmodium falciparum. While high blood levels have been associated with protection against severe malarial disease, they may also contribute to the pathophysiology of cerebral malaria and severe anaemia. Promoter variants in the inducible nitric oxide synthase (iNOS) gene have been shown to influence NO concentrations and disease manifestation. However, findings are conflicting. We examined associations of plasma NO metabolites (NOx) with symptoms of severe malaria, particularly malarial anaemia and cerebral malaria, and with iNOS promoter variants. In 210 Ghanaian children with severe malaria, we measured plasma nitrite, nitrate, and S-nitrosothiol, and genotyped the iNOS promoter variants -954G-->C, -1173C-->T, and the -2.5 kb (CCTTT)(n) microsatellite. NOx levels decreased with age. In young children (<24 months), high NOx was associated with reduced parasite density. This was not seen in patients of 24-48 months of age and reversed in older children. Subgroup analysis revealed that in children with severe anaemia but without cerebral involvement (prostration, impaired consciousness, convulsions), high NOx levels correlated with low parasitaemia (P = 0.02). In these children, elevated NOx levels were also associated with the iNOS-954C-->T/(CCTTT)(8) haplotype (P = 0.03). No association between NOx or iNOS genotypes and cerebral malaria was observed. Our findings suggest that in young children with severe malaria NOx reduces parasitaemia. This effect wanes at higher ages and may reflect a predominance of unspecific immune responses to infection in early childhood. This finding may have importance for the understanding of associations between iNOS variants and severe malaria in regions of differing disease manifestation.
一氧化氮（NO）对恶性疟原虫具有毒性作用。虽然高血药浓度与预防严重疟疾疾病有关，但它们也可能导致脑型疟疾和严重贫血的病理生理过程。诱导型一氧化氮合酶（iNOS）基因的启动子变异已被证明会影响NO浓度和疾病表现。然而，研究结果相互矛盾。我们研究了血浆NO代谢物（NOx）与严重疟疾症状，特别是疟疾贫血和脑型疟疾，以及与iNOS启动子变异之间的关联。在210名患有严重疟疾的加纳儿童中，我们测量了血浆亚硝酸盐、硝酸盐和S-亚硝基硫醇，并对iNOS启动子变异-954G→C、-1173C→T以及-2.5 kb（CCTTT）（n）微卫星进行了基因分型。NOx水平随年龄降低。在幼儿（<24个月）中，高NOx与寄生虫密度降低有关。在24-48个月大的患者中未观察到这种情况，而在年龄较大的儿童中则相反。亚组分析显示，在患有严重贫血但无脑部受累（虚脱、意识障碍、惊厥）的儿童中，高NOx水平与低寄生虫血症相关（P = 0.02）。在这些儿童中，升高的NOx水平也与iNOS-954C→T/（CCTTT）（8）单倍型相关（P = 0.03）。未观察到NOx或iNOS基因型与脑型疟疾之间的关联。我们的研究结果表明，在患有严重疟疾的幼儿中，NOx可降低寄生虫血症。这种作用在较高年龄时减弱，可能反映了幼儿期对感染的非特异性免疫反应占主导地位。这一发现可能对理解不同疾病表现地区iNOS变异与严重疟疾之间的关联具有重要意义。
