Defining the Molecular Determinants of Encephalitic Alphavirus Viremia

定义脑炎甲病毒血症的分子决定因素

• 批准号: 10599124
• 负责人: Stephanie Ander
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599124
• 关键词: Ablation; Alphavirus; Alphavirus Infections; Americas; Antibody Response; Arboviruses; Arthritogenic; Arthropod Vectors; Back; Biochemical; Birds; Blood Vessels; Charge; Circulation; Comparative Study; Cotton Rats; Culicidae; Data; Dependence; Development; Disease; EEEV glycoprotein E2; Ecology; Encephalitis Viruses; Equine Encephalomyelitis; Equus caballus; Excision; Experimental Models; Glycoproteins; Goals; Human; IFNAR1 gene; Immunologics; In Vitro; Infection; Intravenous; Kinetics; Knockout Mice; Knowledge; Kupffer Cells; Laboratories; Liver; Maintenance; Mediating; Molecular; Mus; Nature; Phagocytes; Phenotype; Population; Positioning Attribute; Property; Public Health; Resistance; Risk Factors; Robin bird; Rodent; Role; SR-A proteins; Sequence Analysis; Signal Transduction; Sturnus vulgaris; Surface; Time; Vaccines; Venezuelan; Venezuelan Equine Encephalitis Virus; Viral; Viral reservoir; Viremia; Virion; Virus; Zoonoses; conditional knockout; experimental study; glycoprotein E2 VEE; in vivo Model; innate immune mechanisms; mortality; mouse model; mutant; nervous system disorder; particle; pathogen; response; scavenger receptor; screening; transmission process; type I interferon receptor; vector transmission; virus host interaction

PROJECT SUMMARY This proposal is a comparative study on the development of viremia during encephalitic alphavirus infection and the innate immune mechanisms that mediate clearance of circulating virus in the time before the specific antibody response. Eastern- (EEEV) and Venezuelan- (VEEV) equine encephalitis viruses are mosquito- transmitted zoonoses of high public health concern due to their ability to spill-over into human and equine populations, causing neurologic disease and mortality for which no specific treatments are available. Endemic to the Americas, their natural reservoirs are avian (EEEV) and rodent populations (VEEV). Natural transmission of these and other arboviruses is dependent on the development of a viremia of sufficient amplitude and duration within vertebrate hosts. And while arboviruses are capable of replicating (and causing disease) within several vertebrate species, not all hosts support transmission back to the arthropod vector. Yet, the molecular mechanisms that dictate arboviral viremia in amplifying and “dead-end” hosts are poorly defined. My preliminary findings have identified interesting contrasts from previous studies in Dr. Morrison's laboratory on the vascular clearance of arthritogenic alphaviruses. In particular, I found that intravenous-inoculated EEEV particles are cleared from murine circulation, while VEEV-IAB particles escape vascular clearance. My preliminary data on EEEV clearance from circulation supports a central role for phagocytic cells in the control of alphavirus viremia, however, in contrast to arthritogenic alphaviruses, EEEV vascular clearance occurs with slower kinetics and is independent of class A scavenger receptors (SR). I hypothesize EEEV vascular clearance is mediated by a non-class A SR expressed on liver KC which recognizes a surface-exposed basic patch in the viral E2 glycoprotein, and VEEV-IAB escape from clearance is similarly determined by the absence of a surface-exposed basic residue in E2. Moreover, I hypothesize vascular clearance phenotypes of EEEV and VEEV are host-species dependent and correlate with the distinct vertebrate hosts that support the maintenance of these independent viral populations in nature. My proposed studies will: (i) define the host and viral molecular mechanisms by which EEEV is cleared by a non-class A SR, (ii) assess the fate of EEEV particles following vascular clearance, (iii) identify biochemical properties of VEEV virions that determine murine vascular clearance, and (iv) elucidate mechanisms that define viremia in amplifying versus “dead-end” hosts. The knowledge gained from these studies may help identify risk factors for severe disease and aid the development of new treatments or vaccines against EEEV and VEEV.

项目概要 该提案是对脑炎甲病毒感染期间病毒血症发展的比较研究 以及在特定病毒出现之前介导清除循环病毒的先天免疫机制 东部马脑炎病毒（EEEV）和委内瑞拉马脑炎病毒（VEEV）是蚊子病毒。 由于能够蔓延到人类和马身上，因此引起高度公共卫生关注的人畜共患病 人群，导致神经系统疾病和死亡，而没有特定的治疗方法。 对于美洲，它们的天然宿主是鸟类（EEEV）和啮齿类动物（VEEV）。 这些和其他虫媒病毒的传播取决于病毒血症的发展 脊椎动物宿主内的振幅和持续时间虽然虫媒病毒能够复制（并引起）。 在一些脊椎动物物种中，并非所有宿主都支持传播回节肢动物媒介。 在扩增宿主和“死端”宿主中决定虫媒病毒血症的分子机制尚不清楚。 我的初步发现与莫里森博士实验室之前的研究发现了有趣的对比 我特别发现静脉注射的 EEEV 对血管清除率的影响。 颗粒从小鼠循环中清除，而 VEEV-IAB 颗粒则逃脱血管清除。 EEEV 从循环中清除的初步数据支持吞噬细胞在控制中的核心作用 然而，与致关节炎的甲病毒相比，EEEV 血管清除发生在 动力学较慢并且独立于 A 类清道夫受体 (SR)。 清除是由肝脏 KC 上表达的非 A 类 SR 介导的，该 SR 可识别表面暴露的碱性物质 病毒 E2 糖蛋白中的补丁，并且 VEEV-IAB 逃避清除同样由 E2 中不存在表面暴露的碱性残基。 EEEV 和 VEEV 依赖于宿主物种，并与支持该物种的不同脊椎动物宿主相关。 我提议的研究将：（i）确定宿主和在自然界中维持这些独立的病毒种群。 非 A 类 SR 清除 EEEV 的病毒分子机制，(ii) 评估 EEEV 的命运 血管清除后的颗粒，(iii) 识别 VEEV 病毒粒子的生化特性，这些特性决定 小鼠血管清除率，以及（iv）阐明定义病毒血症放大与“死端”的机制 从这些研究中获得的知识可能有助于识别严重疾病的危险因素并帮助治疗。 开发针对 EEEV 和 VEEV 的新疗法或疫苗。