Viral microRNA effects on pathogenesis of polyomavirus SV40 infections in syrian golden hamsters.
Viral microRNA effects on pathogenesis of polyomavirus SV40 infections in syrian golden hamsters.
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DOI：
10.1371/journal.ppat.1003912
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Butel JS
中科院分区：
文献类型：
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作者：
Zhang S;Sroller V;Zanwar P;Chen CJ;Halvorson SJ;Ajami NJ;Hecksel CW;Swain JL;Wong C;Sullivan CS;Butel JS
多瘤病毒SV 40 microRNA对体内病毒感染发病机制的影响尚不清楚。叙利亚金仓鼠是研究SV 40的小动物模型。我们在这里报告的影响SV 40 microRNA和SV 40 DNA水平在体内的动态调控区的结构的影响。通过心内途径向远交年轻成年仓鼠接种1×107个空斑形成单位的4种不同SV 40变体。感染后3至270天处死感染动物，通过实时定量聚合酶链反应测定不同组织中的病毒DNA载量。所有SV 40毒株均显示频繁建立持续感染和缓慢的病毒清除。SV 40具有广泛的组织嗜性，感染的组织包括肝、肾、脾、肺和脑。肝脏和肾脏含有比其他组织更高的病毒DNA载量;肾脏是长期持续感染的首选部位，尽管可检测到的病毒也保留在肝脏中。在野生型SV 40感染的组织中证实了SV 40 microRNA的表达。MicroRNA阴性突变病毒在肝脏和肾脏中产生的病毒DNA载量始终高于野生型SV 40。具有复杂调控区的病毒在肾脏中显示出比具有简单调控区的病毒略高的病毒DNA载量。在肝脏和肾脏中检测到的早期病毒转录本水平高于晚期转录本。很少检测到感染性病毒。有有限的证据表明microRNA缺陷病毒的清除率增加。SV 40的野生型和microRNA阴性突变体显示出相似的体外小鼠细胞转化率和体内断奶仓鼠肿瘤诱导率。该报告确定了SV 40在仓鼠体内的广泛组织嗜性，并提供了SV 40 microRNA在体内表达和功能的第一个证据。病毒microRNA抑制了由具有简单或复杂调控区的SV 40毒株感染的组织中的病毒DNA水平。最近发现的病毒编码的微小RNA（miRNA）提出了参与病毒复制，免疫识别和宿主细胞存活的其他调节过程的可能性。在这项研究中，我们试图描述SV 40编码的miRNA和病毒调控区的结构对远交叙利亚金黄仓鼠感染的影响。结果显示，SV 40具有广泛的组织嗜性，包括肝、肾、脾、肺和脑，其中肾是长期持续感染的首选部位。在miRNA阴性突变株中观察到组织相关病毒DNA载量的显著增加，而SV 40 miRNA的存在对肿瘤诱导没有影响，对病毒清除几乎没有影响。我们的研究结果提供了第一个证据SV 40 miRNA在体内动物模型中的表达和功能，并强调了SV 40病毒复制和持续感染调控的复杂性。
Effects of polyomavirus SV40 microRNA on pathogenesis of viral infections in vivo are not known. Syrian golden hamsters are the small animal model for studies of SV40. We report here effects of SV40 microRNA and influence of the structure of the regulatory region on dynamics of SV40 DNA levels in vivo. Outbred young adult hamsters were inoculated by the intracardiac route with 1×107 plaque-forming units of four different variants of SV40. Infected animals were sacrificed from 3 to 270 days postinfection and viral DNA loads in different tissues determined by quantitative real-time polymerase chain reaction assays. All SV40 strains displayed frequent establishment of persistent infections and slow viral clearance. SV40 had a broad tissue tropism, with infected tissues including liver, kidney, spleen, lung, and brain. Liver and kidney contained higher viral DNA loads than other tissues; kidneys were the preferred site for long-term persistent infection although detectable virus was also retained in livers. Expression of SV40 microRNA was demonstrated in wild-type SV40-infected tissues. MicroRNA-negative mutant viruses consistently produced higher viral DNA loads than wild-type SV40 in both liver and kidney. Viruses with complex regulatory regions displayed modestly higher viral DNA loads in the kidney than those with simple regulatory regions. Early viral transcripts were detected at higher levels than late transcripts in liver and kidney. Infectious virus was detected infrequently. There was limited evidence of increased clearance of microRNA-deficient viruses. Wild-type and microRNA-negative mutants of SV40 showed similar rates of transformation of mouse cells in vitro and tumor induction in weanling hamsters in vivo. This report identified broad tissue tropism for SV40 in vivo in hamsters and provides the first evidence of expression and function of SV40 microRNA in vivo. Viral microRNA dampened viral DNA levels in tissues infected by SV40 strains with simple or complex regulatory regions. The recent discovery of virally encoded microRNAs (miRNAs) raises the possibility of additional regulatory processes being involved in viral replication, immune recognition, and host cell survival. In this study, we sought to characterize the effect of SV40-encoded miRNAs and the structure of the viral regulatory region on infections in outbred Syrian golden hamsters. Results revealed that SV40 has a wide tissue tropism, including liver, kidney, spleen, lung, and brain, with kidney the preferred site for long-term persistent infection. Significant increases in tissue-associated viral DNA loads were observed with miRNA-negative mutant strains, whereas the presence of SV40 miRNAs had no effect on tumor induction and little effect on viral clearance. Our results provide the first evidence for SV40 miRNA expression and function in an in vivo animal model and highlight the complexity of regulation of SV40 viral replication and persistent infections.
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