Interferon-alpha and MxA inhibit BK polyomavirus replication by interaction with polyomavirus large T antigen

Hsin-Hsu Wu; Yi-Jung Li; Cheng-Hao Weng; Hsiang-Hao Hsu; Ming-Yang Chang; Huang-Yu Yang; Chih-Wei Yang; Ya-Chung Tian

doi:10.1016/j.bj.2023.100682

Interferon-alpha and MxA inhibit BK polyomavirus replication by interaction with polyomavirus large T antigen

Biomed J. 2023 Dec 6:100682. doi: 10.1016/j.bj.2023.100682. Online ahead of print.

Authors

Hsin-Hsu Wu¹, Yi-Jung Li², Cheng-Hao Weng², Hsiang-Hao Hsu², Ming-Yang Chang², Huang-Yu Yang², Chih-Wei Yang², Ya-Chung Tian³

Affiliations

¹ Kidney Research Center, Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taiwan; Department of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taiwan.
² Kidney Research Center, Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taiwan; Department of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Kidney Research Center, Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taiwan; Department of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: dryctian@cgmh.org.tw.

PMID: 38065365
DOI: 10.1016/j.bj.2023.100682

Abstract

Introduction: BK Polyomavirus (BKPyV) infection is a common complication in kidney transplant recipients and can result in poor outcome and graft failure. Currently, there is no known effective antiviral agent. This study investigated the possible antiviral effects of Interferon alpha (IFNα) and its induced protein, MxA, against BKPyV.

Methods: In vitro cell culture experiments were conducted using human primary renal proximal tubular epithelial cells (HRPTECs). We also did animal studies using Balb/c mice with unilateral kidney ischemic reperfusion injury.

Results: Our results demonstrated that IFNα effectively inhibited BKPyV in vitro and murine polyomavirus in animal models. Additionally, IFNα and MxA were found to suppress BKPyV TAg and VP1 production. Silencing MxA attenuated the antiviral efficacy of IFNα.We observed that MxA interacted with BKPyV TAg, causing it to remain in the cytosol and preventing its nuclear translocation. To determine MxA's essential domain for its antiviral activities, different mutant MxA constructs were generated. The MxA mutant K83A retained its interaction with BKPyV TAg, and its antiviral effects were intact. The MxA T103A mutant, on the other hand, abolished GTPase activity and lost its protein-protein interaction with BKPyV TAg, and lost its antiviral effect.

Conclusion: IFNα and its downstream protein, MxA, have potent antiviral properties against BKPyV. Furthermore, our findings indicate that the interaction between MxA and BKVPyV TAg plays a crucial role in determining the anti-BKPyV effects of MxA.

Keywords: BK polyomavirus; Interferon; Kidney transplant; MxA.