Natural infection of norovirus and sapovirus in a birth cohort in a Peruvian periurban community

 描述(申请人提供)：诺沃克病毒(NV)是全球所有年龄段患者腹泻的主要原因。NV是仅次于轮状病毒的儿童胃肠炎和腹泻住院的第二大最常见原因，估计每年导致20万人死亡。当广泛实施轮状病毒疫苗接种时，新城疫很可能成为儿童腹泻住院和死亡的主要原因。然而，新城疫对幼儿的真正负担和获得性免疫力的程度仍然不完全清楚。人类NV感染分为两个主要的基因组组(GI和GII)，以及至少36个基因类型。对NV感染的敏感性被认为是由病毒与组织血型抗原结合所介导的，其作为受体的特异性因NV基因而异。GII4型(GII4型)在有数据的暴发和零星感染中占主导地位。在过去十年中，由于NV主要衣壳蛋白的突变改变了结合位点的配置，并使人能够在一种令人联想到流感的流行病学模式中逃避群体免疫，因此检测到了一系列不断演变的GII.4变异。NV遗传学提出的主要问题包括交叉反应的范围和持续时间、基因和GII.4变种特异性免疫，以及对疫苗设计和测试的影响。我们建议在秘鲁利马的一个城市周边社区进行一项新生儿队列研究，我们自20世纪80年代以来一直在那里工作，以在自然NV感染频繁的情况下解决这些问题。我们与埃默里大学的合作提供了进入领先的NV实验室的途径，该实验室拥有评估自然获得性免疫的专业知识和最先进的试剂。我们从新生儿开始，因为首次感染发生在生命的早期。我们的初步数据显示，遗传异质性比通常假设的要高得多：共鉴定出18种不同的基因类型，其中40%是GII.4，包括5种不同的变异体。相同基因或GII 4变异的重复感染很少见，这表明获得性基因特异性免疫。我们建议通过这项建议来扩展我们对幼儿地方性腹泻的新城疫流行病学的知识，以解决有效疫苗设计和部署的关键问题。我们将量化NV基因在轻、中度胃肠炎中的作用，并通过将血清、唾液和粪便中的NV抗体与NV疾病、感染、脱落长度和直线生长相关联来评估保护性免疫的获得。此外，我们将评估萨博拉病毒作为肠道病原体的作用，并将探索使用社区污水监测来追踪正在传播的病毒株。

 DESCRIPTION (provided by applicant): Norovirus (NV) is the leading cause of diarrhea in patients of all ages worldwide. After rotavirus, NV is the 2nd most frequent cause of pediatric gastroenteritis and hospitalizations for diarrhea, and is estimated to cause 200,000 annual deaths. When rotavirus vaccination is broadly implemented, NV is likely to become the leading cause of pediatric diarrheal hospitalization and deaths. However, the true burden of NV in young children and the extent of acquired immunity remain incompletely understood. Human NV infections are divided into two predominant genogroups (GI and GII), and at least 36 genotypes. Susceptibility to NV infection is thought to be mediated by viral binding to histo-blood group antigens, whose specificity as receptors varies by NV genotype. GII type 4 (GII.4) predominates in outbreaks and sporadic infections for which data are available. An evolving series of GII.4 variants has been detected over the past decade, due to mutations in the major NV capsid protein that change the configuration of the binding site and enable evasion of herd immunity in an epidemiological pattern reminiscent of influenza. Major questions raised by the genetics of NV include the extent and duration of cross-reacting, genotype- and GII.4 variant-specific immunity, and the implications for vaccine design and testing. We propose to conduct a newborn cohort study in a peri-urban community of Lima, Peru, where we have worked since the 1980s, to address these questions in a setting of frequent natural NV infection. Our collaboration with Emory University provides access to a leading NV laboratory with the expertise and state-of-the-art reagents to evaluate naturally-acquired immunity. We begin with newborns because first infections occur very early in life. Our preliminary data demonstrate much higher genetic heterogeneity than is assumed to be the norm: 18 different genotypes were identified of which 40% were GII.4, including 5 different variants. Repeat infections with the same genotype or GII.4 variant were rare, suggesting acquired genotype-specific immunity. We proposed to extend our knowledge of NV epidemiology in endemic diarrhea in young children with this proposal to address issues key to effective vaccine design and deployment. We will quantify the role of NV genotypes in mild and moderate gastroenteritis and evaluate acquisition of protective immunity by correlating serum, saliva and stool antibodies to NVs with NV disease, infection, length of shedding and linear growth. In addition, we will evaluate the role of sapoviru as an enteric pathogen, and will explore the use of community sewage surveillance to track circulating viral strains.