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.

项目摘要 这一建议是一个比较研究的发展病毒血症在脑炎甲病毒感染 和先天免疫机制，介导清除循环病毒的时间之前，具体的 抗体反应。东方-（EEEV）和委内瑞拉-（VEEV）马脑炎病毒是蚊子- 传播的人畜共患病，由于其能够扩散到人类和马， 这些疾病会导致神经系统疾病和死亡，对此没有特定的治疗方法。地方性 到美洲，它们的天然宿主是鸟类（EEEV）和啮齿动物种群（VEEV）。自然 这些和其他虫媒病毒的传播依赖于足够的病毒血症的发展， 振幅和持续时间内脊椎动物宿主。虽然虫媒病毒能够复制（并导致 疾病）在几种脊椎动物物种中，并不是所有的宿主都支持传播回节肢动物载体。然而， 在扩增和“死端”宿主中决定虫媒病毒病毒血症的分子机制还不清楚。 我的初步发现与之前在莫里森博士实验室的研究形成了有趣的对比 对血管清除致关节炎甲病毒的影响特别是，我发现静脉注射EEEV 颗粒从鼠循环中清除，而VEEV-IAB颗粒逃脱血管清除。我 关于EEEV从循环中清除的初步数据支持吞噬细胞在对照中的中心作用。 然而，与致关节炎的甲病毒相反，EEEV血管清除发生在 较慢的动力学和独立的A类清道夫受体（SR）。我假设EEEV血管 清除由肝KC上表达的非A类SR介导，该SR识别表面暴露的碱性磷酸酶。 在病毒E2糖蛋白中的补丁，并且VEEV-IAB逃避清除类似地由 E2中不存在表面暴露的碱性残基。此外，我假设血管清除表型 EEEV和VEEV是宿主种属依赖性的，并且与支持EEEV的不同脊椎动物宿主相关。 在自然界中维持这些独立的病毒群体。我建议的研究将：（一）定义主机， EEEV被非A类SR清除的病毒分子机制，（ii）评估EEEV的命运 （iii）确定VEEV病毒粒子的生化特性， 小鼠血管清除率，和（iv）阐明在扩增与“死端”中定义病毒血症的机制 hosts.从这些研究中获得的知识可能有助于确定严重疾病的风险因素， 开发针对EEEV和VEEV的新治疗或疫苗。