Mechanisms of Antibody-Mediated Neutralization of Flavivirus Infection

黄病毒是一组正链RNA病毒，因其广泛分布和在人类中引起严重疾病的能力而对全球公共卫生产生影响。该属中的几种病毒，如登革热病毒(DENV)和西尼罗河病毒(WNV)，被认为是新出现或重新出现的病原体，因为在过去十年中观察到发病率和死亡率显著增加。据估计，每年有3.9亿人感染四种DENV血清型中的一种，导致约25万例严重和潜在致命的出血性表现。西尼罗河病毒是一种脑炎性黄病毒，于1999年传入北美，随后在整个大陆传播。西尼罗河病毒现在在美国是地方性的。2012年在德克萨斯州发生的西尼罗河病毒局部剧烈暴发的可能性对公共卫生构成了重大威胁。此外，尽管与其他病毒性传染病相比，西尼罗河病毒的临床负担似乎不大，但对在急性西尼罗河病毒感染中幸存下来的个人的发病率的长期研究表明，北美西尼罗河病毒疾病的真正临床负担可能尚未实现。 体液免疫是宿主抵御黄病毒的一个关键方面；激发保护性抗体是正在进行的几种此类病毒疫苗开发工作的主要重点，包括西尼罗河病毒和登革热病毒。使这些努力复杂化的是，自然感染或疫苗接种产生的抗体有可能调节DENV的发病机制并增强疾病。抗体依赖的感染增强(ADE)描述了在抗体或免疫血清的亚中和浓度存在的情况下，携带Fc-γ受体的细胞的感染显著增加。保护性抗体反应的生化和功能特性尚不清楚。 VPS的一个主要目标是了解对黄病毒的体液免疫机制。我们正在研究抗体介导的中和和增强黄病毒感染的分子和结构基础，同时努力应用这些研究产生的知识和观点来剖析自然感染和接种疫苗的人类多克隆抗体反应的功能特性。

Flaviviruses are a group of positive-stranded RNA viruses that have a global impact on public health due to their widespread distribution and ability to cause severe disease in humans. Several viruses in this genus, such as dengue (DENV) and West Nile (WNV) viruses, are considered emerging or re-emerging pathogens due to significant increases in morbidity and mortality observed during the past decade. Each year, an estimated 390 million individuals are infected by one of the four serotypes of DENV, resulting in roughly 250,000 cases of a severe and potentially fatal hemorrhagic manifestation of the disease. WNV is an encephalitic flavivirus introduced into North America in 1999 that has subsequently spread across the continent. WNV is now endemic in the United States. The potential for focal intense outbreaks of WNV, as occurred in 2012 in Texas, represents a significant threat to public health. Furthermore, while the clinical burden of WNV appears modest by comparison to other viral infectious diseases, long-term studies of morbidity in individuals that survive acute WNV infection suggest the true clinical burden of WNV disease in North America may not yet be realized. Humoral immunity is a critical aspect of host protection against flaviviruses; eliciting protective antibodies is a primary focus of ongoing vaccine development efforts for several of these viruses, including WNV and DENV. Complicating these efforts is the potential for antibodies elicited by natural infection or vaccination to modulate DENV pathogenesis and enhance disease. Antibody-dependent enhancement of infection (ADE) describes a dramatic increase in the infection of Fc-gamma-receptor-bearing cells in the presence of sub-neutralizing concentrations of antibody or immune sera. The biochemical and functional properties of a protective antibody response are not known. A primary goal of the VPS is to understand the mechanisms of humoral immunity against flaviviruses. We are investigating the molecular and structural basis of antibody-mediated neutralization and enhancement of flavivirus infection, while working to apply the knowledge and perspectives arising from these studies toward dissecting the functional properties of the polyclonal antibody response of naturally infected and vaccinated humans.