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.

项目摘要/摘要 Bunyaviruses（订单：Bunyaviruses）是一个不断发展且多样化的动物和人类病原体家族 大流行可能性。由于300多名成员以及由于 气候变化，这些病毒负责增加人类疾病的爆发，并提出 对人类健康的重大威胁。裂谷发烧病毒（RVFV）是研究良好的Bunyaviruses之一，是 被指定为NIAID类别A病原体，并将其包括在WHO的优先疾病的蓝图中。这 流行备忘创新联盟（CEPI）包括RVFV作为其新兴传染性的一部分 疾病疫苗计划进一步强调了对全球健康和经济的潜在影响。 Oropouche病毒（OROV）在南美发现，并引起了30多个大型流行病，导致 超过500,000例人类病例，使其成为南美第二大最常见的arboviral疾病 登革热。但是，由于误诊Oropouche发烧，真实案例数可能更高 作为基孔肯雅或登革热。 La Crosse病毒（LACV）的第三名成员在北美发现了主要成员 在美国，小儿病毒脑炎的主要原因。 Orov和LACV也没有 在我们对Bunyavirus发病机理的广泛理解中，Studiod为RVFV，因此存在很大的差距。 目前尚无批准的治疗药物用于治疗RVFV，OROV或LACV疾病，进一步 强调了我们提出的研究的需求。为了满足这种需求，我们进行了一个基因组屏幕， 定义了一些关键因素，包括LRP1，LDL家庭成员。在支持中，我们提供了引人注目的 初步数据，包括在LRP1中的体外验证，足够和缺乏细胞，移植研究， RVFV糖蛋白GN体外直接相互作用。我们还表明，内源性抑制LRP1 来自进化不同宿主的多个细胞系中的体外配体，体内数据证明了 LRP1对于小鼠病毒性疗法和疾病的重要性。在这里，我们将表征LRP1的重要性 进入多个Bunyavirus，定义分子机制，并在体外和体内验证显着性。 这项工作将由具有各个方面的专业知识的高产和协作研究人员进行 拟议的研究，包括生物化学，病毒发病机理，免疫学，蛋白质组学，结构生物学， 和病毒学。完成后，我们希望将LRP1验证为Pan-Bunyavirus进入因子，以填补关键空白 领域并为治疗发展提供新的目标。