Mechanisms of Antibody-Mediated Neutralization of Flavivirus Infection

黄病毒是一组正链RNA病毒，由于其广泛分布和在人类中引起严重疾病的能力，对公共卫生具有全球影响。由于在过去十年中观察到的发病率和死亡率的显著增加，该属中的几种病毒，如登革热（DENV）和西尼罗河（WNV）病毒，被认为是新兴或重新出现的病原体。每年，估计有3.9亿人感染DENV的四种血清型之一，导致大约250，000例该疾病的严重和潜在致命的出血性表现。西尼罗河病毒是一种脑炎黄病毒，于1999年引入北美，随后在整个大陆传播。西尼罗河病毒现在在美国流行。2012年在德克萨斯州发生的西尼罗河病毒集中爆发的可能性对公共卫生构成重大威胁。此外，虽然与其他病毒感染性疾病相比，西尼罗河病毒的临床负担似乎是适度的，但对急性西尼罗河病毒感染存活个体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。 体液免疫是宿主保护免受黄病毒感染的一个关键方面;引发保护性抗体是针对这些病毒中的几种病毒（包括WNV和DENV）正在进行的疫苗开发工作的主要焦点。使这些努力复杂化的是由自然感染或疫苗接种引起的抗体调节DENV发病机制和增强疾病的潜力。抗体依赖性感染增强（ADE）描述了在亚中和浓度的抗体或免疫血清存在下携带Fc-γ受体的细胞的感染的显著增加。保护性抗体反应的生物化学和功能特性尚不清楚。 VPS的主要目标是了解抗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，同时致力于应用这些研究所产生的知识和观点，以解剖自然感染和接种疫苗的人的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.