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- Title
Tumor necrosis factor-alpha blockade suppresses BK polyomavirus replication.
- Authors
Li, Yi-Jung; Wang, Jiun-Wen; Wu, Hsin-Hsu; Wang, Hsu-Han; Chiang, Yang-Jen; Yang, Huang-Yu; Hsu, Hsiang-Hao; Yang, Chih-Wei; Tian, Ya-Chung
- Abstract
Purpose: BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-α blockade on BKPyV infection. Methods: Urine specimens from 22 patients with BKPyV-associated nephropathy (BKPyVN) and 35 non-BKPyVN kidney transplant recipients were analyzed. Results: We demonstrated increased urinary levels of TNF-α and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-α stimulated the expression of large T antigen and viral capsid protein-1 mRNA and proteins and BKPyV promoter activity. Knockdown of TNFR1 or TNFR2 expression caused a reduction in TNF-α-stimulated viral replication. NF-κB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-κB binding site. The addition of a NF-κB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-α functionality by etanercept reduced BKPyV-stimulated expression of TNF-α, interleukin-1β (IL-1β), IL-6 and IL-8 and suppressed TNF-α-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-α, interleukin-1 β (IL-1β), IL-6 and TNFR1 and TNFR2 but the stimulated magnitude was far less than that induced by poly(I:C). This may suggest that BKPyV-mediated autocrine effect is not a major source of TNFα. Conclusion: TNF-α stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target.
- Subjects
KIDNEY disease risk factors; KIDNEY disease prevention; POLYOMAVIRUS diseases; INTERLEUKINS; CLINICAL trials; ANTI-inflammatory agents; NF-kappa B; POLYOMAVIRUSES; TREATMENT effectiveness; RISK assessment; GENE expression; RESEARCH funding; URINALYSIS; PHARMACODYNAMICS; DISEASE complications
- Publication
Infection, 2023, Vol 51, Issue 4, p967
- ISSN
0300-8126
- Publication type
Article
- DOI
10.1007/s15010-022-01962-0