The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output.
The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output.
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DOI：
10.1371/journal.ppat.1000496
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发表时间：
2009-07
期刊：
影响因子：
6.7
通讯作者：
Thorley-Lawson DA
中科院分区：
文献类型：
--
作者：
Hadinoto V;Shapiro M;Sun CC;Thorley-Lawson DA
为了开发更详细的EBV持续模型，我们研究了健康携带者中病毒脱落的动力学。我们证明，EB病毒进入唾液是连续和快速的，以至于病毒水平在≤2分钟内被取代，这是正常个体吞咽的平均时间。因此，口腔不是病毒的储存库，而是一条管道，源源不断的病毒在唾液中流经。因此，病毒的排泄率比之前认为的要高得多，这个水平太高了，不能仅用Waldeyer环中B细胞的复制来解释。病毒脱落在短时间内(几小时到几天)相对稳定，但在较长时间内变化在3.5到5.5个对数之间，这种变化程度也不能仅仅用B细胞中的复制来解释。这种差异意味着，与人们普遍认为的相反，脱落率的高低并不是个人之间的差异，而是个人内部随着时间的推移而变化的函数。脱落的动力学描述了一个控制病毒产生的过程，该过程在任何时刻≤3次独立发生。这个过程以指数级增长，然后随机终止。我们认为，这些动态可以用单个B细胞零星释放病毒的模型来最好地解释，病毒感染任何地方，从1到5个上皮细胞。这种感染以恒定的指数速度传播，并随机终止，导致感染的上皮细胞斑块，大小从1到105个细胞不等。在任何时候都有极少量的斑块(≤3)。我们认为，这些斑块的最终大小是淋巴上皮内感染传播率的函数，淋巴上皮内的感染传播率可能由组织的结构复杂性决定，但最终受到免疫反应的限制。爱泼斯坦-巴尔病毒是一种人类病原体，与几种人类癌症有关，但作为一种潜伏感染，在大多数成年人中仍然存在。EBV持续性的特征是血液中存在潜伏感染的细胞，并将病毒排放到唾液中。我们首次提出了对病毒脱落的系统定量分析。我们证明，与之前认为的相反，对于所有测试的受试者来说，脱落是连续的，并且处于高水平。这种传染性病毒的持续存在可能是EBV相关肿瘤鼻咽癌发生的重要危险因素。与血液中的受感染细胞不同，血液中的受感染细胞多年来一直保持非常稳定的水平，我们表明，病毒的脱落是高度可变的，因此在任何时候，任何个人都可能是相对较高或较低的脱落者。我们用一个简单的仿真模型对这些动力学进行了数学分析。我们发现，它们可以用一个简单的指数函数来解释，我们假设它是1-3个上皮细胞斑块的扩张。
To develop more detailed models of EBV persistence we have studied the dynamics of virus shedding in healthy carriers. We demonstrate that EBV shedding into saliva is continuous and rapid such that the virus level is replaced in ≤2 minutes, the average time that a normal individual swallows. Thus, the mouth is not a reservoir of virus but a conduit through which a continuous flow stream of virus passes in saliva. Consequently, virus is being shed at a much higher rate than previously thought, a level too high to be accounted for by replication in B cells in Waldeyer's ring alone. Virus shedding is relatively stable over short periods (hours-days) but varies through 3.5 to 5.5 logs over longer periods, a degree of variation that also cannot be accounted for solely by replication in B cells. This variation means, contrary to what is generally believed, that the definition of high and low shedder is not so much a function of variation between individuals but within individuals over time. The dynamics of shedding describe a process governing virus production that is occurring independently ≤3 times at any moment. This process grows exponentially and is then randomly terminated. We propose that these dynamics are best explained by a model where single B cells sporadically release virus that infects anywhere from 1 to 5 epithelial cells. This infection spreads at a constant exponential rate and is terminated randomly, resulting in infected plaques of epithelial cells ranging in size from 1 to 105 cells. At any one time there are a very small number (≤3) of plaques. We suggest that the final size of these plaques is a function of the rate of infectious spread within the lymphoepithelium which may be governed by the structural complexity of the tissue but is ultimately limited by the immune response. Epstein-Barr virus is a human pathogen associated with several human cancers that nevertheless persists benignly as a latent infection in the majority of adults. EBV persistence is characterized by the presence of latently infected cells in the blood and the shedding of virus into saliva. We present the first systematic quantitative analysis of virus shedding. We show, contrary to what was previously thought, that shedding is continuous and at a high level for all subjects tested. This constant presence of infectious virus may be a crucial risk factor in the development of the EBV-associated tumor nasopharyngeal carcinoma. Unlike infected cells in the blood, which are maintained at very stable levels for years, we show that virus shedding is highly variable such that at any time any individual may be a relatively high or low shedder. We have analyzed these dynamics mathematically and with a simple simulation model. We find that they can be explained by a simple exponential function which we hypothesize is the expansion of 1–3 plaques of epithelial cells.
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