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，对公共卫生产生全球性影响。由于在过去十年中观察到发病率和死亡率显著增加，该属的一些病毒，如登革热（DENV）和西尼罗河（WNV）病毒被认为是新发或再发病原体。每年，估计有3.9亿人感染登革热病毒的四种血清型之一，导致大约25万例严重和可能致命的出血热病例。西尼罗河病毒是1999年传入北美的一种脑炎黄病毒，随后在整个大陆传播。西尼罗河病毒现在在美国流行。像2012年在德克萨斯州发生的那样，西尼罗河病毒有可能发生局灶性强烈暴发，这对公共卫生构成重大威胁。此外，虽然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，但对急性西尼罗河病毒感染存活个体发病率的长期研究表明，北美地区西尼罗河病毒疾病的真正临床负担可能尚未实现。

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 towards dissecting the functional properties of the polyclonal antibody response of naturally infected and vaccinated humans.