Multiple host barriers restrict poliovirus trafficking in mice.
Multiple host barriers restrict poliovirus trafficking in mice.
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DOI：
10.1371/journal.ppat.1000082
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发表时间：
2008-06-06
期刊：
影响因子：
6.7
通讯作者：
Pfeiffer JK
中科院分区：
文献类型：
--
作者：
Kuss SK;Etheredge CA;Pfeiffer JK
RNA病毒（如脊髓灰质炎病毒）具有高突变率，并且可能需要多样化的病毒种群才能获得完整的毒力。我们先前确定了表达人脊髓灰质炎病毒受体（PVR）的小鼠外周注射后脊髓灰质炎病毒传播的局限性，我们假设宿主干扰素应答可能导致病毒瓶颈。在这里，我们检查了PVR小鼠和缺乏干扰素α/β受体（PVR-IFNAR-/-）（先天免疫的重要组成部分）的PVR小鼠中脊髓灰质炎病毒种群瓶颈。为了监测种群动态，我们开发了一个由10种标记脊髓灰质炎病毒组成的库，通过一种新的基于杂交的检测方法进行区分。在肌肉内或腹腔内注射10种病毒合并物后，在PVR小鼠中观察到转运至脑的主要瓶颈，但在PVR-IFNAR−/−小鼠中不存在，表明干扰素应答是外周部位至脑瓶颈的决定因素。由于脊髓灰质炎病毒通过粪-口途径感染人类，我们测试了PVR-IFNAR−/−小鼠经口接种后是否存在瓶颈。尽管外周注射PVR-IFNAR−/−小鼠后缺乏瓶颈，但我们在经口接种动物中发现了主要瓶颈，表明物理屏障可能导致经口瓶颈。有趣的是，我们发现的三个主要瓶颈中的两个通过用葡聚糖硫酸钠预处理小鼠而部分克服，葡聚糖硫酸钠会损伤结肠上皮。总的来说，我们发现病毒从肠道运输到其他身体部位，包括CNS，是一个非常动态的随机过程。我们认为，多个宿主屏障和由此产生的有限的脊髓灰质炎病毒种群多样性可能有助于解释罕见的病毒中枢神经系统入侵和麻痹性脊髓灰质炎的发生。这些天然宿主屏障可能在限制许多微生物的传播方面发挥作用。RNA病毒非常容易出错，并且可以利用其复制的不精确性来适应受感染宿主内的复杂环境。然而，病毒种群可能会遇到瓶颈，这限制了它们的多样性，并可能降低它们的毒力。我们假设自然屏障可能限制RNA病毒在受感染宿主内的传播。为了验证这一假设，我们设计了一个由10种标记脊髓灰质炎病毒组成的库，这些病毒可以通过一种新的检测方法识别，通过注射或口服接种感染易感小鼠，并确定了10种病毒成功传播到包括大脑在内的各种身体部位的百分比。我们发现，平均而言，只有10%-20%的输入病毒被发现在大多数组织中，这表明屏障阻止了整个种群的传播。一个这样的物理屏障，结肠上皮细胞的重要性，在实验中证明，结肠在口服接种前被损坏。在这些条件下，30%-50%的输入病毒成功地传播到身体的各个部位。我们认为，宿主屏障限制了病毒的传播，这可能解释了由于中枢神经系统侵袭而导致的麻痹性脊髓灰质炎的罕见发病率。
RNA viruses such as poliovirus have high mutation rates, and a diverse viral population is likely required for full virulence. We previously identified limitations on poliovirus spread after peripheral injection of mice expressing the human poliovirus receptor (PVR), and we hypothesized that the host interferon response may contribute to the viral bottlenecks. Here, we examined poliovirus population bottlenecks in PVR mice and in PVR mice that lack the interferon α/β receptor (PVR-IFNAR−/−), an important component of innate immunity. To monitor population dynamics, we developed a pool of ten marked polioviruses discriminated by a novel hybridization-based assay. Following intramuscular or intraperitoneal injection of the ten-virus pool, a major bottleneck was observed during transit to the brain in PVR mice, but was absent in PVR-IFNAR−/− mice, suggesting that the interferon response was a determinant of the peripheral site-to-brain bottleneck. Since poliovirus infects humans by the fecal–oral route, we tested whether bottlenecks exist after oral inoculation of PVR-IFNAR−/− mice. Despite the lack of a bottleneck following peripheral injection of PVR-IFNAR−/− mice, we identified major bottlenecks in orally inoculated animals, suggesting physical barriers may contribute to the oral bottlenecks. Interestingly, two of the three major bottlenecks we identified were partially overcome by pre-treating mice with dextran sulfate sodium, which damages the colonic epithelium. Overall, we found that viral trafficking from the gut to other body sites, including the CNS, is a very dynamic, stochastic process. We propose that multiple host barriers and the resulting limited poliovirus population diversity may help explain the rare occurrence of viral CNS invasion and paralytic poliomyelitis. These natural host barriers are likely to play a role in limiting the spread of many microbes. RNA viruses are highly error prone, and can use their replication infidelity to adapt to complex environments within an infected host. However, viral populations may experience bottlenecks, which limit their diversity and potentially reduce their virulence. We hypothesized that natural barriers may limit the spread of RNA viruses within an infected host. To test this hypothesis, we engineered a pool of ten marked polioviruses identifiable by a novel assay, infected susceptible mice by injection or oral inoculation, and determined the percentage of the ten viruses that successfully spread to various body sites, including the brain. We found that, on average, only 10%–20% of the input viruses were found in most tissues, suggesting that barriers prevented the spread of the whole population. The importance of one such physical barrier, the colonic epithelium, was demonstrated in experiments where the colon was damaged prior to oral inoculation. Under these conditions, 30%–50% of the input viruses successfully spread to various body sites. We propose that host barriers limit viral spread, and this could possibly explain the rare incidence of paralytic poliomyelitis due to central nervous system invasion.
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