NITRIC OXIDE AND SEVERE MALARIA

疟疾在全球造成的死亡率高于任何其他寄生虫病 疾病，但疾病的病理生理学的充分理解是 严重疟疾缺乏有效治疗，治疗方法有限。 一氧化氮（NO）在体外对广泛的 包括恶性疟原虫在内的多种微生物。最近， 我们注意到NO的产生和白细胞NO合酶2型增加， （NOS 2）在坦桑尼亚无症状疟疾儿童中的表达。 然而，NO的产生和NOS 2的表达明显减少， 患有脑型疟疾的儿童。 该提案旨在扩大 我们早期的工作是研究导致 严重疾病中NO产生和NOS 2表达的减少， 并确定这些发现是否出现在一个地区的成年人中， 不同的疟疾流行病学。我们将阐明NO和NOS 2的作用 作为严重疟疾的分子标记， 在严重疾病的发病机制中的作用。 我们的目的是（i）确定降低全身NO的机制 严重疟疾中NOS 2的产生和表达;（2）确定 某些NOS 2和细胞因子基因等位基因标记与 严重疟疾，（3）确定NO是否也是逆 其他年龄组疟疾严重程度的分子相关性（成人与 儿童）和疟疾流行病学不同的地区（印度尼西亚 坦桑尼亚）。 实现这些目标将大大增加我们的总体认识 严重疟疾的发病机制。此外，这项工作可能 为治疗和预防严重的 疟疾

Malaria causes more mortality globally than any other parasitic disease, yet a full understanding of disease pathophysiology is lacking, and effective treatments for severe malaria are limited. Nitric oxide (NO) has antimicrobial effects in vitro against a wide variety of microorganisms including Plasmodium falciparum. Recently, we noted increased NO production and leukocyte NO synthase type 2 (NOS2) expression in Tanzanian children with asymptomatic malaria. However, NO production and NOS2 expression were markedly decreased in children with cerebral malaria. This proposal is designed to extend our earlier work to examine the molecular mechanism(s) responsible for the decreases in NO production and NOS2 expression in severe disease, and to determine if these findings are seen in adults in a region with different malaria epidemiology. We will clarify the role of NO and NOS2 as molecular markers in severe malaria and examine their potential roles in the pathogenesis of severe disease. Our aims are to (i) determine the mechanism for decreased systemic NO production and NOS2 expression in severe malaria; (2) determine if there are certain NOS2 and cytokine gene allelic markers associated with severe malaria, and (3) establish whether NO is also an inverse molecular correlate of malaria severity in other age groups (adults vs children) and in regions with different malaria epidemiology (Indonesia vs Tanzania). Accomplishing these goals will add greatly to our overall understanding of the pathogenesis of severe malaria. Furthermore, this work may result in novel strategies for the treatment and prevention of severe malaria.