Characterizing the role of LDL related receptor 1 (Lrp1) as host entry factor for multiple bunyaviruses

描述 LDL 相关受体 1 (Lrp1) 作为多种布尼亚病毒宿主进入因子的作用

• 批准号: 10667857
• 负责人: Gaya K. Amarasinghe
• 金额: $ 78.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-14 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667857
• 关键词: Address; Affinity; Animals; Atherosclerosis; Binding; Biochemical; Biochemistry; Biological; Biology; Bioterrorism; Birds; Brain; Brazil; Bunyavirales; Category A pathogen; Cell Line; Cells; Chikungunya fever; Childhood; Collaborations; Complement; Complex; Coupled; Culicidae; Data; Dengue; Dengue Fever; Disease; Disease Outbreaks; Disease Outcome; Distant; Drug or chemical Tissue Distribution; Emerging Communicable Diseases; Endocytosis; Epidemic; Excision; Family; Family member; Fever; Frequencies; Genomics; Glycoproteins; Health; Human; Human Biology; Immunology; In Vitro; Infection; Insecta; Integration Host Factors; Kidney; Knowledge; LDL-Receptor Related Protein 1; La Crosse virus; Ligands; Lipoprotein Receptor; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Malignant Neoplasms; Mammals; Molecular; Mus; National Institute of Allergy and Infectious Disease; Nature; Neurodegenerative Disorders; North America; Oropouche virus; Orthobunyavirus; Pathogenesis; Peripheral; Pharmacotherapy; Play; Productivity; Proteins; Proteomics; Receptor Cell; Reporting; Reptiles; Research Personnel; Rift Valley fever virus; Role; Route; Sequence Homology; South America; Spleen; Structure; Taxonomy; Testing; Therapeutic; Tissues; Tropism; United States; Vaccines; Validation; Viral; Viral Encephalitis; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Work; arboviral disease; arthropod-borne; chikungunya; climate change; epidemic preparedness; global health; human disease; human pathogen; in vivo; innovation; member; mouse model; new therapeutic target; novel; pandemic potential; pathogen; prevent; programs; receptor; structural biology; therapeutic development; validation studies; vector tick; viral transmission; virology; virus tropism

Project Summary/Abstract Bunyaviruses (Order: Bunyavirales) are a growing and diverse family of animal and human pathogens with pandemic potential. With over 300 members and an expanding distribution of mosquito and tick vectors due to climate change, these viruses are responsible for increasing outbreaks of human disease and present a significant threat to human health. Rift Valley Fever virus (RVFV) is one of the well-studied bunyaviruses and is designated as an NIAID Category A pathogen and included in the WHO’s Blueprint of Priority Diseases. The Coalition for Epidemic Preparedness Innovations (CEPI) included RVFV as part of their emerging infectious diseases vaccine program, further emphasizing the potential impact on the global health and economy. Oropouche virus (OROV) is found in South America and has caused more than 30 large epidemics resulting in over 500,000 human cases, making it the second most common arboviral disease in South America behind Dengue fever. However, the true case number is likely much higher due to Oropouche fever being misdiagnosed as Chikungunya or Dengue. A third member, La Crosse virus (LACV) is found primarily in North America and is the primary cause of pediatric viral encephalitis in the United States. Neither OROV nor LACV have been as well studied as RVFV, and thus a significant gap remains in our broad understanding of bunyavirus pathogenesis. Currently there are no approved therapeutic drugs for treatment of RVFV, OROV, or LACV disease, further highlighting the need for our proposed studies. To address this need, we conducted a genomic screen that defined several critical factors, including Lrp1, an LDL family member. In support we provide compelling preliminary data including in vitro validation in Lrp1 sufficient and deficient cells, transcomplementation studies, and direct interaction between RVFV glycoprotein Gn in vitro. We also show that inhibition of Lrp1 by endogenous ligands in vitro in multiple cell lines from evolutionarily distinct hosts, and in vivo data demonstrating the importance of Lrp1 for viral tropism and disease in mice. Here we will characterize the importance of Lrp1 for entry of multiple bunyaviruses, define molecular mechanisms, and validate the significance in vitro and in vivo. This work will be performed by highly productive and collaborative investigators with expertise in every aspect of the proposed studies, including biochemistry, viral pathogenesis, immunology, proteomics, structural biology, and virology. At completion, we expect to validate Lrp1 as pan-bunyavirus entry factor, filling a key gap in the field and to provide novel targets for therapeutic development.

项目总结/摘要 布尼亚病毒（目的：布尼亚病毒目）是一个不断增长的和多样化的家庭的动物和人类病原体， 大流行的可能性。有300多个成员，蚊子和蜱虫媒介的分布不断扩大， 气候变化，这些病毒是负责增加人类疾病的爆发，并提出了一个 严重威胁人类健康。裂谷热病毒（RVFV）是一种研究充分的布尼亚病毒， 被指定为NIAID A类病原体，并被列入世卫组织的优先疾病蓝图。的 流行病防范创新联盟（CEPI）将RVFV作为其新兴传染病的一部分， 疾病疫苗计划，进一步强调对全球健康和经济的潜在影响。 奥罗波什病毒（Oropouche virus，ORFV）在南美洲发现，已引起30多次大规模流行， 超过500，000例人类病例，使其成为南美洲第二大最常见的虫媒病毒疾病，仅次于 登革热然而，由于奥罗普什热被误诊， 基孔肯雅热或登革热第三个成员，拉克罗斯病毒（LACV）主要在北美发现， 是美国儿童病毒性脑炎的主要病因Occupy和LACV都没有这么好 因此，在我们对布尼亚病毒致病机制的广泛理解中仍然存在显著的差距。 目前，还没有批准的治疗药物用于治疗RVFV、卵巢癌或LACV疾病， 强调了我们建议的研究的必要性。为了满足这一需求，我们进行了基因组筛选， 定义了几个关键因素，包括LDL家族成员Lrp 1。为了支持我们提供令人信服的 初步数据，包括在Lrp 1充足和缺陷细胞中的体外验证，反式互补研究， 以及RVFV糖蛋白Gn之间的直接相互作用。我们还表明，内源性Lrp 1的抑制， 在来自进化上不同的宿主的多个细胞系中的体外配体，以及证明 Lrp 1对小鼠中病毒嗜性和疾病重要性在这里，我们将描述Lrp 1对 多种布尼亚病毒的进入，定义分子机制，并验证体外和体内的意义。 这项工作将由具有各方面专业知识的高效和协作的调查人员进行 拟议的研究，包括生物化学，病毒发病机制，免疫学，蛋白质组学，结构生物学， 和病毒学在完成时，我们希望验证Lrp 1作为泛布尼亚病毒进入因子，填补了研究中的一个关键空白。 并为治疗开发提供新的靶点。