JC Polyomavirus Infection of Primary Human Renal Epithelial Cells Is Controlled by a Type I IFN-Induced Response
JC Polyomavirus Infection of Primary Human Renal Epithelial Cells Is Controlled by a Type I IFN-Induced Response
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DOI：
10.1128/mbio.00903-16
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发表时间：
2016-07-01
期刊：
影响因子：
6.4
通讯作者：
Atwood, Walter J.
中科院分区：
文献类型：
--
作者：
Assetta, Benedetta;De Cecco, Marco;Atwood, Walter J.
JC和BK人多瘤病毒（分别为JCPyV和BKPyV）在肾脏中建立终身持续感染。在免疫抑制的个体中，JCPyV引起进行性多灶性白质脑病（PML），这是一种致命的神经退行性疾病，BKPyV引起多瘤病毒相关肾病（PVN）。在这项研究中，我们比较了JCPyV和BKPyV感染原代人肾近端小管上皮细胞（HRPTE）。JCPyV建立了持续感染，但BKPyV在15天内杀死了细胞。为了确定负责控制JCPyV感染和促进病毒持久性的细胞因子，我们在感染后的几个时间点分析了JCPyV和BKPyV感染细胞的转录组。我们发现，感染两种病毒诱导干扰素的生产，但干扰素刺激的基因（ISGs）只在JCPyV感染的细胞被激活。负责诱导ISG的磷酸化STAT 1和IRF 9易位到JCPyV感染的细胞的细胞核，但在BKPyV感染的细胞中没有。在BKPyV感染的细胞中，诱导了细胞因子信号传导的两个关键抑制因子SOCS 3和SOCS 1。感染BKPyV而不是JCPyV引起PML小体的重组，这与灭活抗病毒应答相关。干扰素受体的阻断和可溶性干扰素α（IFN-α）和IFN-β的中和部分缓解了对JCPyV感染的阻断，导致感染性增强。我们的研究结果表明，I型IFN反应有助于建立持久性感染JCPyV在HRPTE cells.IMPORTANCE人多瘤病毒JCPyV和BKPyV都建立终身持续性感染的肾脏。在免疫抑制的患者中，BKPyV在肾脏中引起显著的病理，但JCPyV仅很少与该器官中的疾病相关。肾脏病理学中这种显著差异背后的原因尚不清楚。在这项研究中，我们表明，感染原代人肾小管上皮细胞与JCPyV和BKPyV的结果在不同的先天免疫反应，控制JCPyV，但不能控制BKPyV。这是第一项直接比较JCPyV和BKPyV在它们自然感染的相同细胞类型中的体外感染的研究，并且已经发现的显著差异可以部分解释不同的疾病结果。
The JC and BK human polyomaviruses (JCPyV and BKPyV, respectively) establish lifelong persistent infections in the kidney. In immunosuppressed individuals, JCPyV causes progressive multifocal leukoencephalopathy (PML), a fatal neurodegenerative disease, and BKPyV causes polyomavirus-associated nephropathy (PVN). In this study, we compared JCPyV and BKPyV infections in primary human renal proximal tubule epithelial (HRPTE) cells. JCPyV established a persistent infection, but BKPyV killed the cells in 15 days. To identify the cellular factors responsible for controlling JCPyV infection and promoting viral persistence, we profiled the transcriptomes of JCPyV- and BKPyV-infected cells at several time points postinfection. We found that infection with both viruses induced interferon production but that interferon-stimulated genes (ISGs) were only activated in the JCPyV-infected cells. Phosphorylated STAT1 and IRF9, which are responsible for inducing ISGs, translocated to the nucleus of JCPyV-infected cells but did not in BKPyV-infected cells. In BKPyV-infected cells, two critical suppressors of cytokine signaling, SOCS3 and SOCS1, were induced. Infection with BKPyV but not JCPyV caused reorganization of PML bodies that are associated with inactivating antiviral responses. Blockade of the interferon receptor and neutralization of soluble interferon alpha (IFN-alpha) and IFN-beta partially alleviated the block to JCPyV infection, leading to enhanced infectivity. Our results show that a type I IFN response contributes to the establishment of persistent infection by JCPyV in HRPTE cells.IMPORTANCE The human polyomaviruses JCPyV and BKPyV both establish lifelong persistent infection in the kidneys. In immunosuppressed patients, BKPyV causes significant pathology in the kidney, but JCPyV is only rarely associated with disease in this organ. The reasons behind this striking difference in kidney pathology are unknown. In this study, we show that infection of primary human renal tubule epithelial cells with JCPyV and BKPyV results in divergent innate immune responses that control JCPyV but fail to control BKPyV. This is the first study that directly compares JCPyV and BKPyV infection in vitro in the same cell type they naturally infect, and the significant differences that have been uncovered could in part explain the distinct disease outcomes.