Nitric Oxide and Severe Malaria

描述（由申请人提供）：疟疾在全球造成的死亡率高于任何其他寄生虫病，但对保护性免疫反应和疾病病理生理学缺乏充分了解，对严重疟疾的有效治疗有限。一氧化氮（NO）在体外对包括恶性疟原虫在内的多种生物具有抗菌作用。此外，一氧化氮在体内还具有抗疟疾作用。我们详细的实地研究（在非洲儿童和印度尼西亚成人中）表明，疾病严重程度与血单核细胞（PBMC）诱导的NO合成酶（NOS2）表达和全身NO生成之间存在高度显著的负相关。我们发现了NOS2和相关基因的新多态性，这些基因与NO的产生和对严重疟疾的抗性显著相关。这项建议旨在继续我们由美国国立卫生研究院资助的工作，以澄清一氧化氮在疟疾临床免疫和预防严重疟疾中的作用。我们将扩大目前在坦桑尼亚和伊里安查亚进行的病例对照研究，以确认我们新发现的多态性与疾病表现和严重程度之间的关联，我们将在健康受试者和疟疾患者中对这些多态性进行功能研究。在对重症和非重症疟疾患者的纵向研究中，我们将探讨宿主PBMC表达NOS2的能力与重症疟疾易感性之间的关系。我们的目标是：(1)在两个不同的人群中表征新型NOS2和相关遗传多态性与疟疾疾病严重程度的关系；(2)确定这些与疟疾相关的NOS2多态性的功能意义（包括体内和体外）；(3)在纵向研究中，确定PBMC NOS2的表达和活性是否与个体对重症疟疾的易感性直接相关。实现我们的既定目标对于增进对宿主对疟疾感染的抵抗力和对严重疟疾的抵抗力的了解将具有非常重要的意义。此外，从这项工作中获得的信息可能适用于其他传染病。

DESCRIPTION (provided by the applicant): Malaria causes more mortality globally than any other parasitic disease, yet a full understanding of protective immune responses and 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 organisms including Plasmodium falciparum. In addition, NO has anti-disease effects against malaria in vivo. Our detailed field studies (in both African children and Indonesian adults) have shown a highly significant inverse association between disease severity and blood mononuclear cell (PBMC) inducible NO synthase (NOS2) expression and systemic NO production. We have discovered novel polymorphisms in NOS2 and related genes that are significantly associated with NO production and resistance to severe malaria. This proposal is designed to continue our NIH-funded work to clarify the role of NO in clinical immunity to malaria and protection from severe malaria. We will extend our current case-control studies in Tanzania and Irian Jaya to confirm the association of our newly identified polymorphisms with disease manifestations and severity, and we will undertake functional studies of these polymorphisms in healthy subjects and those with malaria. In longitudinal studies of patients with both severe and uncomplicated malaria, we will investigate the relationship between the ability of host PBMC to express NOS2 and the susceptibility to severe malaria. Our aims are (1) to characterize the association of novel NOS2 and related genetic polymorphisms with malaria disease severity in two separate populations; (2) to determine the functional significance of these malaria-related NOS2 polymorphisms (both in vitro and in vivo); and (3) in longitudinal studies, to determine whether PBMC NOS2 expression and activity relate directly to an individual's susceptibility to severe malaria. Accomplishing our stated goals will be very significant in adding to the understanding of host resistance to malaria infection and resistance to severe malaria. Also, information learned from this work will likely be applicable to other infectious diseases.