Lauterbach-Rivière Lise, Thuringer Lucia, Feld Pascal, Toews Lina Kathrin, Schüssler Jessica, Klinz Jonas, Gläser Lars, Lohse Stefan, Sternjakob Anna, Gasparoni Gilles, Kattler-Lackes Kathrin, Walter Jörn, Lauterbach Marcel A, Rahmann Sven, Möller Lars, Laue Michael, Janssen Martin, Stöckle Michael, Schmit David, Fliser Danilo, Smola Sigrun
Institute of Virology, Saarland University Medical Center, Homburg, Germany.
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, Saarbrücken, Germany.
J Med Virol. 2025 Feb;97(2):e70210. doi: 10.1002/jmv.70210.
To date, no drugs are approved for BK polyomavirus (BKPyV) reactivation, a major cause of nephropathy after kidney transplantation. Recently, tumor necrosis factor-α (TNF-α) blockade has been proposed as a promising therapy, however, the effect of TNF-α on the clinically most common archetype (ww) BKPyV remained unclear. Assays in primary renal proximal tubule epithelial cells (RPTEC) allowed efficient replication only of BKPyV strains with rearranged (rr) non-coding control regions (NCCR), which may develop at later disease stages, but not of ww-BKPyV. Here, we optimized culture conditions allowing robust replication of patient-derived ww-BKPyV, while efficiently preserving their ww-NCCR. TNF-α promoted rr-BKPyV replication, while the T1 cytokine IFN-γ suppressed it, also in the presence of TNF-α. Surprisingly, TNF-α alone was sufficient to suppress all ww-BKPyV strains tested. Comprehensive analysis using siRNAs, and chimeric or mutated BKPyV-strains revealed that the response to TNF-α depends on the NCCR type, and that the NF-κB p65 pathway but not the conserved NF-κB binding site is essential for the TNF-α-induced enhancement of rr-BKPyV replication. Our data suggest that in immunosuppressed patients with archetype-dominated infections, TNF-α blockade could interfere with natural TNF-α-mediated anti-BKPyviral control, and this could be detrimental when IFN-γ-driven T1 responses are impaired. Ongoing inflammation, however, could lead to the selection of rearrangements responding to NCCR-activating pathways downstream of NF-κB p65 signaling, that may overcome the initial TNF-α-mediated suppression. Our findings also highlight the importance of using clinically relevant BKPyV isolates for drug testing and discovery, for which this new assay paves the way.
迄今为止，尚无药物被批准用于治疗BK多瘤病毒（BKPyV）再激活，这是肾移植后肾病的主要原因。最近，肿瘤坏死因子-α（TNF-α）阻断疗法被认为是一种有前景的治疗方法，然而，TNF-α对临床上最常见的原型（ww）BKPyV的作用仍不清楚。在原代肾近端小管上皮细胞（RPTEC）中的检测仅允许具有重排（rr）非编码控制区（NCCR）的BKPyV毒株有效复制，这种重排可能在疾病后期出现，但ww-BKPyV毒株则不能。在此，我们优化了培养条件，使源自患者的ww-BKPyV能够强劲复制，同时有效保留其ww-NCCR。TNF-α促进rr-BKPyV的复制，而T1细胞因子IFN-γ则抑制其复制，即使在存在TNF-α的情况下也是如此。令人惊讶的是，单独的TNF-α就足以抑制所有测试的ww-BKPyV毒株。使用小干扰RNA（siRNA）以及嵌合或突变的BKPyV毒株进行的综合分析表明，对TNF-α的反应取决于NCCR类型，并且NF-κB p65信号通路而非保守的NF-κB结合位点对于TNF-α诱导的rr-BKPyV复制增强至关重要。我们的数据表明，在以原型为主导感染的免疫抑制患者中，TNF-α阻断可能会干扰天然TNF-α介导的抗BKPyV病毒控制，而当IFN-γ驱动的T1反应受损时，这可能是有害的。然而，持续的炎症可能会导致选择对NF-κB p65信号下游的NCCR激活途径有反应的重排，这可能会克服最初的TNF-α介导的抑制作用。我们的研究结果还强调了使用临床相关的BKPyV分离株进行药物测试和发现的重要性，这种新的检测方法为此铺平了道路。
