Adenovirus Infection of Human Enteroids Reveals Interferon Sensitivity and Preferential Infection of Goblet Cells
Adenovirus Infection of Human Enteroids Reveals Interferon Sensitivity and Preferential Infection of Goblet Cells
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DOI：
10.1128/jvi.00250-18
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发表时间：
2018-05-01
影响因子：
5.4
通讯作者：
Smith, Jason G.
中科院分区：
文献类型：
--
作者：
Holly, Mayumi K.;Smith, Jason G.
人腺病毒（HAdV）是重要的人类病原体。虽然只有一个HAdV血清型的子集通常会引起人类的胃肠炎，但大多数HAdV物种在胃肠道中复制。HAdV和人肠上皮之间复杂相互作用的知识受到缺乏含有相关细胞类型的合适细胞培养系统的限制。最近，这种需要已经满足了稳定和长期培养的原代肠上皮细胞作为肠。人类肠状病毒已被用于揭示轮状病毒，诺如病毒和肠道病毒复制的新的和有趣的方面，促使我们探索其适用于HAdV文化。我们发现肠和非肠HAdV的原型菌株和临床分离株在人类肠中均能有效复制。呼吸道病原体HAdV-5 p和肠道病原体HAdV-41 p对人肠上皮细胞单层中的I型和III型干扰素均敏感，但对A549细胞不敏感。有趣的是，HAdV-5 p，而不是HAdV-41 p，优先感染杯状细胞。并且，HAdV-5 p而不是HAdV-41 p被肠道人α-防御素HD 5有效中和。这些研究突出了HAdV生物学的新方面，这些生物学方面是由原代肠上皮细胞培养独特揭示的。肠道腺病毒是全球儿童胃肠炎的重要原因，但我们对其独特生物学的了解有限。在这里，我们报告了肠道和呼吸道人类腺病毒的原型和临床分离株在肠样组织（一种原代肠道细胞培养系统）中的稳健复制。最近的研究表明，其他挑剔的肠道病毒复制在人类肠。因此，人类类肠病毒可以为培养肠道病毒提供一个统一的平台，有可能从患者中分离出更多样化的病毒。此外，干扰素限制呼吸道腺病毒和肠道腺病毒的能力以及呼吸道血清型对杯状细胞的令人惊讶的偏好都证明了这种培养系统揭示腺病毒生物学方面的能力，这些方面以前用标准细胞系无法实现。
Human adenoviruses (HAdV) are significant human pathogens. Although only a subset of HAdV serotypes commonly cause gastroenteritis in humans, most HAdV species replicate in the gastrointestinal tract. Knowledge of the complex interaction between HAdVs and the human intestinal epithelium has been limited by the lack of a suitable cell culture system containing relevant cell types. Recently, this need has been met by the stable and prolonged cultivation of primary intestinal epithelial cells as enteroids. Human enteroids have been used to reveal novel and interesting aspects of rotavirus, norovirus, and enterovirus replication, prompting us to explore their suitability for HAdV culture. We found that both prototype strains and clinical isolates of enteric and nonenteric HAdVs productively replicate in human enteroids. HAdV-5p, a respiratory pathogen, and HAdV-41p, an enteric pathogen, are both sensitive to type I and III interferons in human enteroid monolayers but not A549 cells. Interestingly, HAdV-5p, but not HAdV-41p, preferentially infected goblet cells. And, HAdV-5p but not HAdV-41p was potently neutralized by the enteric human alpha-defensin HD5. These studies highlight new facets of HAdV biology that are uniquely revealed by primary intestinal epithelial cell culture. IMPORTANCE Enteric adenoviruses are a significant cause of childhood gastroenteritis worldwide, yet our understanding of their unique biology is limited. Here we report robust replication of both prototype and clinical isolates of enteric and respiratory human adenoviruses in enteroids, a primary intestinal cell culture system. Recent studies have shown that other fastidious enteric viruses replicate in human enteroids. Therefore, human enteroids may provide a unified platform for culturing enteric viruses, potentially enabling isolation of a greater diversity of viruses from patients. Moreover, both the ability of interferon to restrict respiratory and enteric adenoviruses and a surprising preference of a respiratory serotype for goblet cells demonstrate the power of this culture system to uncover aspects of adenovirus biology that were previously unattainable with standard cell lines.