de Kort Hanneke, Heutinck Kirstin M, Ruben Jurjen M, Ede V Silva Alessa, Wolthers Katja C, Hamann Jörg, Ten Berge Ineke J M
1 Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2 Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 3 Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands. 4 Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Transplantation. 2017 Aug;101(8):1820-1829. doi: 10.1097/TP.0000000000001521.
BK polyomavirus (BKV)-associated nephropathy is a threat to kidney allograft survival affecting up to 15% of renal transplant patients. Previous studies revealed that tubular epithelial cells (TEC) show a limited response towards BKV infection. Here we investigated the interplay between BKV and TEC in more detail. In particular, we questioned whether BKV suppresses and/or evades antiviral responses.
Human primary TEC and peripheral blood mononuclear cells were infected with BKV Dunlop strain or other viruses. Moreover, TEC were stimulated with genomic double-stranded (ds)DNA or IFN. Viral replication and cellular responses were measured using quantitative real time PCR and multiplex assay.
BKV infection of primary human TEC did not induce an antiviral response, whereas infection with influenza A virus, herpes simplex virus 1, or cytomegalovirus induced a strong antiviral response measured by upregulation of interferon-stimulated genes, such as CXCL10 and DAI. In addition, intracellular delivery of dsDNA or stimulation with IFN did elicit a rapid and pronounced response. However, BKV infection did not affect dsDNA-induced gene expression, indicating BKV did not modulate the antiviral response. Prestimulation of primary TEC with IFNα or dsDNA did not hamper replication of BKV, whereas influenza and herpes simplex virus 1 replication were clearly reduced. In contrast, BKV infection of leukocytes did elicit an antiviral response.
BKV specifically evades innate immunity in TEC and is not susceptible to an intrinsic interferon response, which may facilitate latent presence of the virus in this cell type.
BK多瘤病毒（BKV）相关性肾病是肾移植存活的一个威胁，影响高达15%的肾移植患者。先前的研究表明，肾小管上皮细胞（TEC）对BKV感染的反应有限。在此，我们更详细地研究了BKV与TEC之间的相互作用。特别是，我们质疑BKV是否抑制和/或逃避抗病毒反应。
用人原代TEC和外周血单核细胞感染BKV邓洛普株或其他病毒。此外，用基因组双链（ds）DNA或干扰素刺激TEC。使用定量实时PCR和多重检测法测量病毒复制和细胞反应。
人原代TEC感染BKV未诱导抗病毒反应，而甲型流感病毒、单纯疱疹病毒1或巨细胞病毒感染则通过上调干扰素刺激基因（如CXCL10和DAI）诱导强烈的抗病毒反应。此外，dsDNA的细胞内递送或干扰素刺激确实引发了快速而明显的反应。然而，BKV感染并未影响dsDNA诱导的基因表达，表明BKV未调节抗病毒反应。用IFNα或dsDNA对原代TEC进行预刺激并未阻碍BKV的复制，而流感病毒和单纯疱疹病毒1的复制则明显减少。相反，白细胞感染BKV确实引发了抗病毒反应。
BKV在TEC中特异性逃避先天免疫，且不易受到内源性干扰素反应的影响，这可能有助于该病毒在这种细胞类型中潜伏存在。
