Norwalk-like Viruses and Their Receptors

描述(申请人提供)：诺瓦克样病毒(NLV)是单链、正向RNA病毒，可导致人类急性胃肠炎。这些病毒具有高度传染性，对环境条件具有抵抗力，并通过表面接触或人际传播迅速传播。NLV通常在各种环境中引起大规模的食物和水传播暴发，无论是民用还是军用。由于缺乏细胞培养和动物模型，对NLV的研究一直很困难。目前还没有治疗NLV感染的方法，NLV的高度遗传和抗原多样性使得很难通过接种疫苗来预防这种疾病。我们最近观察到原型诺沃克病毒(NV)使用人类组织血型抗原作为感染的受体。这一发现为制定控制NLV疾病的战略开辟了一条道路。广泛的研究表明，不同的NLV识别由分泌者、Lewis和ABO类型定义的不同受体。含有这些主要组织血液表位的糖结合物被发现与NLV结合有关，在母乳喂养的婴儿中发现了类似的糖结合物，以防止NLV感染。因此，人类组织血型抗原在宿主对NLV感染的特异性中起着关键作用。阻断NLV附着/进入肠上皮细胞的抑制剂可能被开发为一种有效的抗NLV药物。针对这一未来目标，提出了以下三个具体目标。具体目的1.鉴定诺瓦克样病毒(NLV)的遗传变异性及其与人类组织血型抗原的结合，以扩大毒株多样性。具体目的2.通过计算机模拟和生物化学方法定位与人组织血型抗原结合的NLV衣壳结构域(S)。具体目的3.在有无人类组织血型抗原的情况下，确定NLV衣壳和亚衣壳单位的晶体结构。

DESCRIPTION (provided by applicant): Norwalk-like viruses (NLVs) are single-stranded, positive-sense RNA viruses that cause acute gastroenteritis in humans. The viruses are highly contagious, resistant to environmental conditions, and spread quickly by surface contact or person-to-person transmission. NLVs commonly cause large food- and water-borne outbreaks in a variety of settings, both civilian and military. NLVs have been difficult to study due to the lack of cell culture and animal models. There is no treatment available for NLV infection and the high genetic and antigenic diversity of NLVs makes it difficult to prevent the disease by a vaccination. We have recently observed that the prototype Norwalk virus (NV) uses the human histo-blood group antigens as receptors for infection. This discovery opens a way to develop strategies to control NLV disease. Extended studies showed that different NLVs recognize different receptors defined by secretor, Lewis, and ABO types. Glycoconjugates containing these major histo-blood epitopes were found to be responsible for NLV binding and similar glycoconjugates found in human milk protected breast-fed infants from NLV infection. Thus, human histo-blood group antigens play a critical role in the host specificity to NLV infection. Inhibitors that block NLV attachment/entry to intestinal epithelial cells may be developed as an effective antiviral drug against NLVs. Towards this future goal, the following three specific aims are proposed. Specific aim 1. To characterize the genetic variability of Norwalk-like viruses (NLVs) and their binding to human histo-blood group antigens for extended strain diversity. Specific aim 2. To map the domain(s) of NLV capsids that bind to human histo-blood group antigens by computer modeling and biochemistry approaches. Specific aim 3. To determine the crystal structure of NLV capsid and sub-capsid units in the presence and absence of human histo-blood group antigens.