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

HIV/疟疾混合感染对免疫功能障碍和血脑屏障的影响

基本信息

批准号：
8287171
负责人：
Sarah E Hochman
金额：
$ 14.92万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-23 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8287171
关键词：
Address Adhesions Affect Africa South of the Sahara African Animal Model Antibodies Astrocytes Binding Blood - brain barrier anatomy Brain C57BL/6 Mouse CD4 Lymphocyte Count CD4 Positive T Lymphocytes Cause of Death Cell Communication Cells Cerebral Malaria Cessation of life Child Clinical Clinical Course of Disease Clinical Treatment Cognitive Coma Complex Data Dementia Development Disease Endothelial Cells Endothelium Erythrocytes Evaluation Experimental Models Goals HIV HIV Infections HIV Seropositivity HIV-1 Human Human immunodeficiency virus test Immune Immune Cell Activation Immune System Diseases Immune response Immune system Impairment In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Response Intervention Lead Lymphocyte Malaria Mediating Minor Modeling Molecular Mononuclear Mus Myeloid Cells Neurocognitive Neurologic Organ Outcome Parasitemia Pathogenesis Pathology Peripheral Peripheral Blood Mononuclear Cell Permeability Plasmodium falciparum Production Proviruses Research Personnel Risk Rodent Model Severities Severity of illness Surface T-Lymphocyte Testing Time Transgenic Mice Vascular Endothelium Viral Load result Viremia Work brain cell cell motility cyclin T1 cytokine design effective therapy falls global health immune function improved in vitro Model in vivo inflammatory marker migration monocyte motor disorder mouse model novel patient population population based promoter public health relevance trafficking

项目摘要

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.

描述（由调查员提供）：每年有 5 亿人感染疟疾，100 万人死于疟疾，其中大多数死亡是非洲儿童死于脑疟疾。在撒哈拉以南非洲地区，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，并且一种感染对另一种感染病程的影响可能会对全球健康产生影响。 HIV和疟疾与宿主免疫系统的相互作用各不相同，导致免疫细胞的复杂激活，以及随后严格调节的细胞因子和抗体的产生。虽然早期基于人群的研究表明，HIV 阳性和阴性疟疾患者之间的结果没有差异，但最近的研究表明，HIV 感染者有症状的疟疾发作更频繁，而 HIV 感染者的疟疾会增加 HIV 病毒血症并减少 CD4+ T 细胞。合并感染对中枢神经系统病理学的影响，包括脑型疟疾和艾滋病毒相关的神经认知障碍，尚不清楚。我们假设艾滋病毒和疟疾共同感染会加剧宿主的免疫反应，这种免疫失调解释了疾病临床谱的差异。在本提案中，我们将利用已建立的体外和体内实验模型来研究联合感染导致免疫失调的机制以及这如何影响内皮激活和血脑屏障功能。公共卫生相关性：疟疾和艾滋病毒都影响着发展中国家的数百万人。大多数疟疾死亡是由于撒哈拉以南非洲儿童的脑型疟疾造成的，那里大约有 2440 万人感染艾滋病毒，其中包括 200 万儿童。最近的研究表明，HIV 感染者更频繁地出现症状性疟疾，并且与疟疾合并感染会增加 HIV 病毒血症并减少 CD4+ T 细胞。我们建议研究疟疾和艾滋病毒如何相互作用，从而改变免疫功能和严重疟疾（包括脑型疟疾）的发展，以及艾滋病毒相关神经认知障碍的进展。我们的长期目标是开发干预措施，改善受疟疾和艾滋病毒影响的个体的临床结果。