The Mammalian NRAMP family as Alphavirus Pathogenesis Determinants

哺乳动物 NRAMP 家族作为甲病毒发病机制的决定因素

• 批准号: 8853780
• 负责人: Jennifer Elizabeth Jones
• 金额: $ 3.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853780
• 关键词: Affect; Alphavirus; Alphavirus Infections; Americas; Antarctica; Arthralgia; Automobile Driving; Binding; Birds; Brain; Caribbean region; Cell Surface Proteins; Cells; Centers for Disease Control and Prevention (U.S.); Chikungunya virus; Clinical; Culicidae; Data; Dendritic Cells; Development; Disease; Disease Outbreaks; Disease Outcome; Disease susceptibility; Embryo; Encephalitis; Epidemic; Event; Fibroblasts; Geographic Locations; Human; ITGAX gene; In Vitro; Infection; Insecta; Integration Host Factors; Ions; Knockout Mice; Lead; Left; Mammalian Cell; Measures; Molecular; Mus; Myeloid Cells; Natural Resistance; Neurologic; Neurons; Nramp protein; Pain; Pathogenesis; Play; Population; Predisposition; Preventive; Process; Protein Family; Proteins; Relative (related person); Resistance; Role; Ross river virus; Saints; Severities; Sindbis Virus; Source; Specificity; Sum; Tamoxifen; Testing; Time; Tissues; Training; Tropism; Vaccines; Venezuelan Equine Encephalitis Virus; Viral; Viral Encephalitis; Virus; Virus Diseases; Virus Replication; Work; alphavirus receptor; cell type; cellular targeting; design; divalent metal; human disease; in vitro Model; in vivo; in vivo Model; macrophage; mouse model; natural resistance-associated macrophage protein 1; new therapeutic target; overexpression; pathogen; protein expression; public health relevance; receptor; success; symptom management; therapeutic development; therapeutic vaccine; transmission process; vector; vector control; vector mosquito; virus host interaction; virus pathogenesis; virus tropism

DESCRIPTION (provided by applicant): Alphaviruses such as Chikungunya virus (CHIKV) and Venezuelan equine encephalitis virus (VEEV) are important emerging human pathogens known to cause explosive epidemics. These viruses are responsible for outbreaks of viral encephalitis or painful recurring arthralgia in humans. Each year they have the potential to spread from a mosquito or avian reservoir to new regions. Large sums have been invested in vector surveillance and symptom management, but therapeutics and vaccines that protect against alphavirus infection have had limited success. Our group studies the pathogenesis of alphaviruses in vivo, including CHIKV and Sindbis virus (SINV). These kinds of studies can contribute to the design of more effective therapeutics and vaccines through an enhanced understanding of the molecular events that occur during infection. Our LONG-TERM GOAL is to understand the exact mechanisms of alphavirus interactions with their hosts. In this proposal, we investigate the interaction between SINV and two related receptors, mammalian NRAMP 1 and 2. Infection of mammalian cells by the alphavirus Sindbis virus (SINV) requires natural resistance-association macrophage protein 2 (NRAMP2) for entry. However, this requirement has never been evaluated in vivo. Further, the interaction between SINV and the closely related and functionally similar NRAMP1 protein has never been evaluated. Therefore, our OBJECTIVE in this study is to define the consequence of NRAMP2 utilization on SINV pathogenesis and to determine whether a similar role exists for NRAMP1. We HYPOTHESIZE that the mammalian NRAMP proteins are important determinants of SINV tropism and pathogenesis. To achieve our objective, we have proposed the following aims. In SPECIFIC AIM 1, we will analyze the role of NRAMP2 in host susceptibility to disease and virus tropism. We will achieve this aim using tissue- specific and inducible NRAMP2 knockout mouse models. In SPECIFIC AIM 2, we will investigate whether NRAMP1 functions as an additional entry receptor during SINV infection. We will use an in vitro model to overexpress NRAMP1 and define the relative utilization of mouse or human NRAMP 1 versus NRAMP2 by SINV. These studies will define the precise impact of mammalian NRAMP expression on SINV infection and disease. Successful completion of these aims could indicate that the NRAMP proteins are appropriate and novel therapeutic targets. The proposed study provides the applicant with an excellent source of training in virus-host interactions that impact alphavirus pathogenesis.

描述（由申请人提供）：基孔肯雅病毒（CHIKV）和委内瑞拉马脑炎病毒（VEEV）等甲病毒是重要的新兴人类病原体，已知会引起爆炸性流行病。这些病毒是导致人类病毒性脑炎或复发性关节痛爆发的原因。每年它们都有可能从蚊子或鸟类宿主传播到新的地区。人们在病媒监测和症状管理方面投入了大量资金，但预防甲病毒感染的治疗方法和疫苗却取得了有限的成功。 我们小组研究甲病毒的体内发病机制，包括CHIKV和辛德比斯病毒（SINV）。此类研究可以通过增强对感染过程中发生的分子事件的了解，有助于设计更有效的治疗方法和疫苗。我们的长期目标是了解甲病毒与其宿主相互作用的确切机制。在本提案中，我们研究了 SINV 与两种相关受体（哺乳动物 NRAMP 1 和 2）之间的相互作用。甲病毒辛德比斯病毒 (SINV) 感染哺乳动物细胞需要天然抵抗相关巨噬细胞蛋白 2 (NRAMP2) 的进入。然而，这一要求从未在体内进行过评估。此外，SINV 与密切相关且功能相似的 NRAMP1 蛋白之间的相互作用从未得到评估。因此，我们本研究的目的是确定 NRAMP2 利用对 SINV 发病机制的影响，并确定 NRAMP1 是否存在类似的作用。我们假设哺乳动物 NRAMP 蛋白是 SINV 趋向性和发病机制的重要决定因素。 为了实现我们的目标，我们提出了以下目标。在 SPECIFIC AIM 1 中，我们将分析 NRAMP2 在宿主对疾病和病毒向性的易感性中的作用。我们将使用组织特异性和可诱导的 NRAMP2 敲除小鼠模型来实现这一目标。在 SPECIFIC AIM 2 中，我们将研究 NRAMP1 是否在 SINV 感染期间充当额外的进入受体。我们将使用体外模型来过表达 NRAMP1，并定义 SINV 对小鼠或人类 NRAMP 1 与 NRAMP2 的相对利用。这些研究将明确哺乳动物 NRAMP 表达对 SINV 感染和疾病的精确影响。这些目标的成功完成可能表明 NRAMP 蛋白是合适的新型治疗靶点。拟议的研究为申请人提供了影响甲病毒发病机制的病毒与宿主相互作用的良好培训来源。