PMID- 36512270 OWN - NLM STAT- MEDLINE DCOM- 20230719 LR - 20230719 IS - 1439-0973 (Electronic) IS - 0300-8126 (Print) IS - 0300-8126 (Linking) VI - 51 IP - 4 DP - 2023 Aug TI - Tumor necrosis factor-alpha blockade suppresses BK polyomavirus replication. PG - 967-980 LID - 10.1007/s15010-022-01962-0 [doi] AB - PURPOSE: BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-alpha (TNF-alpha) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-alpha 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-alpha and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-alpha 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-alpha-stimulated viral replication. NF-kappaB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-kappaB binding site. The addition of a NF-kappaB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-alpha functionality by etanercept reduced BKPyV-stimulated expression of TNF-alpha, interleukin-1beta (IL-1beta), IL-6 and IL-8 and suppressed TNF-alpha-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-alpha, interleukin-1 beta (IL-1beta), 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 TNFalpha. CONCLUSION: TNF-alpha stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target. CI - (c) 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany. FAU - Li, Yi-Jung AU - Li YJ AD - Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, No 5, Fusing St., Taoyuan, 333, Taiwan. AD - Department of Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Wang, Jiun-Wen AU - Wang JW AD - Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, No 5, Fusing St., Taoyuan, 333, Taiwan. AD - Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Wu, Hsin-Hsu AU - Wu HH AD - Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, No 5, Fusing St., Taoyuan, 333, Taiwan. AD - Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan. FAU - Wang, Hsu-Han AU - Wang HH AD - Department of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan. FAU - Chiang, Yang-Jen AU - Chiang YJ AD - Department of Medicine, Chang Gung University, Taoyuan, Taiwan. AD - Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan. FAU - Yang, Huang-Yu AU - Yang HY AD - Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, No 5, Fusing St., Taoyuan, 333, Taiwan. AD - Department of Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Hsu, Hsiang-Hao AU - Hsu HH AD - Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, No 5, Fusing St., Taoyuan, 333, Taiwan. AD - Department of Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Yang, Chih-Wei AU - Yang CW AD - Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, No 5, Fusing St., Taoyuan, 333, Taiwan. AD - Department of Medicine, Chang Gung University, Taoyuan, Taiwan. FAU - Tian, Ya-Chung AU - Tian YC AD - Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, No 5, Fusing St., Taoyuan, 333, Taiwan. dryctian@cgmh.org.tw. AD - Department of Medicine, Chang Gung University, Taoyuan, Taiwan. dryctian@cgmh.org.tw. LA - eng GR - CMRPG3K0592/Chung Gang Medical Research Project/ GR - CMRPG3H0601/Chung Gang Medical Research Project/ GR - NRRPG3J6023/National Science Council of Taiwan/ PT - Journal Article DEP - 20221213 PL - Germany TA - Infection JT - Infection JID - 0365307 RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (Receptors, Tumor Necrosis Factor, Type II) RN - 0 (NF-kappa B) RN - 0 (Interleukin-6) SB - IM MH - Humans MH - *BK Virus/genetics MH - Tumor Necrosis Factor-alpha MH - Receptors, Tumor Necrosis Factor, Type I MH - Receptors, Tumor Necrosis Factor, Type II/genetics MH - NF-kappa B MH - Interleukin-6 MH - *Polyomavirus Infections/metabolism/pathology MH - Inflammation PMC - PMC9745287 OTO - NOTNLM OT - BK polyomavirus OT - BKPyV-associated nephropathy OT - Large T antigen OT - Nuclear factor-kappaB OT - Tumor necrosis factor-alpha COIS- All authors declare no conflict of interest. No financial or non-financial interests are directly or indirectly related to the work. EDAT- 2022/12/14 06:00 MHDA- 2023/07/19 06:43 PMCR- 2022/12/13 CRDT- 2022/12/13 11:22 PHST- 2022/07/19 00:00 [received] PHST- 2022/12/05 00:00 [accepted] PHST- 2023/07/19 06:43 [medline] PHST- 2022/12/14 06:00 [pubmed] PHST- 2022/12/13 11:22 [entrez] PHST- 2022/12/13 00:00 [pmc-release] AID - 10.1007/s15010-022-01962-0 [pii] AID - 1962 [pii] AID - 10.1007/s15010-022-01962-0 [doi] PST - ppublish SO - Infection. 2023 Aug;51(4):967-980. doi: 10.1007/s15010-022-01962-0. Epub 2022 Dec 13.