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

总体摘要 人星状病毒（HAstV）是感染性腹泻的主要原因。然而，目前的“金本位” 诊断试验不能检测与人类感染相关的HAstV基因型的2/3， HAstV感染不仅诊断不足，而且比认识到的更普遍。也有所 越来越多的人认识到HAstV疾病可以从无症状到严重甚至致命的全身性 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炭疽病也不像教条所要求的那样简单 相信然而，不同HAstV基因型在疾病中的作用目前尚不清楚，迄今为止还没有研究表明， 定义了与星状病毒相关性结肠炎相关的宿主或病毒因素。 我们提出的研究开始，以填补这一空白的知识，是第一个工作，旨在了解 HAstV相关腹泻：从流行病学到基础病毒学。强有力的初步研究表明， 不同的病毒基因型在儿科肿瘤患者中共同传播，男孩的可能性是男孩的四倍。 感染者比女孩多，从患者身上分离的病毒具有不同的体外表型。因此， 我们计划研究的目标是开始了解HAstV相关的腹泻在一个新的高风险， 人口我们的中心假设是，星状病毒引起肠道疾病的能力在很大程度上取决于 由它们广泛的异质性和独特的生物学行为介导。为了验证我们的核心假设，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肠胃炎的关系。 2.确定牙周病是否与体外表型相关。 3.是否存在其他HAstV基因型？ 鉴于我们在星状病毒生物学方面的专业知识， 具有星状病毒感染的最高风险的儿科肿瘤患者队列， 访问广泛的元数据，包括疟疾的发病/存在。重要的是，我们已经 证明了我们的队列感染了来自所有3个分支的基因型，现在我们将能够 确定它们与乳腺癌的关系。有趣的是，男性似乎更倾向于性别偏见， 很可能是甲肝病毒阳性将产生大量新的基因组信息，这些信息对 许多调查员。从长远来看，这些研究可能会揭示有关公共卫生的重要新信息。 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.