HIV/Malaria Coinfection Effects on Immune Dysfunction and the Blood-Brain Barrier

描述（由调查人员提供）：每年有5亿人感染疟疾，100万人死于疟疾，其中大多数死亡是由于非洲儿童的脑疟疾。在撒哈拉以南非洲，大约有2440万人感染艾滋病毒，其中包括200万儿童。因此，数百万人面临同时感染艾滋病毒和疟疾的风险，一种感染对另一种感染的病程的影响可能对全球健康产生影响。HIV和疟疾都与宿主的免疫系统产生独特的相互作用，导致免疫细胞的复杂激活，随后严格调节细胞因子和抗体的产生。虽然早期基于人群的研究显示艾滋病毒阳性和阴性疟疾患者之间的结果没有差异，但最近的工作表明，艾滋病毒感染者有更频繁的症状性疟疾发作，而艾滋病毒感染者的疟疾会增加艾滋病毒血症并减少CD4+ T细胞。合并感染对中枢神经系统病理的影响，包括脑疟疾和艾滋病毒相关的神经认知障碍，尚不清楚。我们假设HIV和疟疾的共同感染加剧了宿主的免疫反应，这种免疫失调解释了疾病临床谱的差异。在本提案中，我们将使用已建立的体外和体内实验模型来检查共同感染导致免疫失调的机制以及这如何影响内皮细胞激活和血脑屏障功能。

DESCRIPTION (provided by investigator): Each year, 500 million are infected and 1 million die because of malaria, with most deaths due to cerebral malaria in African children. In sub-Saharan Africa, roughly 24.4 million people have HIV, including 2 million children. Thus, millions are at risk for coinfection with both HIV and malaria, and effects of one infection on the disease course of the other may have global health implications. HIV and malaria each interact with the host's immune system uniquely, resulting in complex activations of immune cells, and subsequent tightly regulated production of cytokines and antibodies. While early population-based studies showed no difference in outcomes between HIV-positive and negative individuals with malaria, more recent work suggests HIV-infected people have more frequent episodes of symptomatic malaria and malaria in those with HIV increases HIV viremia and decreases CD4+ T cells. The effects of co-infection on CNS pathology, including cerebral malaria and HIV-associated neurocognitive disorders, are not known. We hypothesize that HIV and malaria co-infection exacerbates the host immune response, and that this immune dysregulation explains differences in the clinical spectrum of disease. In this proposal, we will use established in vitro and in vivo experimental models to examine the mechanisms by which co-infection causes immune dysregulation and how this impacts endothelial activation and blood-brain barrier function. PUBLIC HEALTH RELEVANCE: Both malaria and HIV affect millions of people in the developing world. The majority of malaria deaths are due to cerebral malaria in children in sub-Saharan Africa, where roughly 24.4 million people are infected with HIV, including 2 million children. Recent work suggests HIV-infected people have more frequent episodes of symptomatic malaria, and co-infection with malaria increases HIV viremia and decreases CD4+ T cells. We propose to study how malaria and HIV interact to alter immune function and development of severe malaria including cerebral malaria, as well as progression of HIVassociated neurocognitive disorders. Our long-term goal is to develop interventions that improve clinical outcomes in individuals affected by both malaria and HIV.