Do they or don't they: astrovirus-induced diarrhea

总体摘要 人类星状病毒(HAstV)是感染性腹泻的主要原因。然而，目前的“黄金标准” 诊断测试未能检测到与人类感染有关的2/3的HAstV基因类型，因此很可能 HAstV感染不仅被低估，而且比人们认识到的更普遍。也有一种 越来越多的人认识到HAstV疾病可以是无症状的，也可以是严重的，甚至是致命的系统性疾病 腹泻以外的疾病，包括脑炎和脑膜炎，特别是在高危人群中 这表明与星状病毒相关的腹泻疾病也不像教条所说的那样简单。 相信我。然而，不同的HAstV基因型在疾病中的作用目前尚不清楚，到目前为止还没有研究 定义了与星状病毒相关性腹泻疾病有关的宿主或病毒因素。 我们提议的研究开始填补这一知识空白，成为第一个旨在理解 HAstV相关性腹泻：从流行病学到基础病毒学。强有力的初步研究表明， 多种病毒基因型在儿童肿瘤患者中共同循环，男孩患上这种疾病的可能性是男性的四倍 从患者身上分离的病毒在体外有不同的表型。因此，总体上， 我们计划的研究的目标是开始了解HAstV相关性腹泻在一种新的高危疾病中的作用 人口。我们的中心假设是，星状病毒引起腹泻的能力在很大程度上是 由它们广泛的异质性和独特的生物学行为所介导。为了测试我们的中心假设，我们有 提出了以下三个相互关联但又相互独立的具体目标： 1.了解星状病毒感染与腹泻病之间的关系。 2.确定腹泻病是否与体外表型相关。 3.是否存在额外的HAstV基因？ 鉴于我们在星状病毒生物学方面的专业知识，以及拥有新颖的 患星状病毒感染风险最高的儿童肿瘤科患者的队列 获取大量元数据，包括腹泻疾病的发病/存在情况。重要的是，我们已经 证明我们的队列感染了所有3个分支的基因类型，现在我们将能够 确定它们与腹泻疾病的关系。有趣的是，男性的性别偏见似乎更大。 很可能是HASTV阳性。将产生大量新的基因组信息，这些信息将对 许多调查人员。从长远来看，这些研究可能会揭示有关公共卫生的关键新信息 病毒性肠道感染的影响。

OVERALL ABSTRACT Human astroviruses (HAstV) are a leading cause of infectious diarrhea. Yet, the current “gold-standard” diagnostic test fails to detect 2/3 of the HAstV genotypes associated with human infection making it likely that HAstV infection is not only under-diagnosed, but more prevalent than appreciated. There has also been an increased appreciation that HAstV disease can range from asymptomatic to significant and even fatal systemic diseases beyond diarrhea including encephalitis and meningitis, particularly in high-risk populations suggesting that astrovirus-associated diarrheal disease is also not as straight-forward as dogma would have us believe. Yet, the role for distinct HAstV genotypes in disease is currently unknown and no studies to date have defined the host or viral factors connected with astroviral-associated diarrheal disease. Our proposed studies begin to fill this gap in knowledge by being the first work aimed at understanding HAstV-associated diarrhea: from epidemiology to basic virology. Strong preliminary studies suggest that diverse viral genotypes co-circulate in pediatric oncology patients with boys being four times more likely to be infected than girls, and that viruses isolated from patients have distinct in vitro phenotypes. Thus, the overall goals of our planned studies are to begin to understand HAstV-associated diarrhea in a novel high-risk population. Our central hypothesis is that the ability of astroviruses to cause diarrheal illness is largely mediated by their broad heterogeneity and distinct biological behaviors. To test our central hypothesis, we have proposed the following three interconnected but independent specific aims: 1. Understand the association between astrovirus infection and diarrheal disease. 2. Determine if diarrheal disease correlates with in vitro phenotypes. 3. Are there additional HAstV genotypes? We are uniquely suited to undertake this work given our expertise in astrovirus biology as well as having novel cohorts of pediatric oncology patients that are among the highest risk for having astrovirus infections with access to extensive metadata including onset/presence of diarrheal disease. Importantly, we have already demonstrated that our cohorts are infected with genotypes from all 3 clades, and now we will be able to determine their association with diarrheal disease. Intriguingly, there appears to be a sex bias with males more likely to be HAstV-positive. Extensive new genomic information will be generated that will be invaluable to many investigators. In the long term, these studies may reveal critical new information on the public health impact of viral enteric infections.