Ischemia-reperfusion injury and immunosuppressants promote polyomavirus replication through common molecular mechanisms

Background Immunosuppressants and renal ischemia-reperfusion injury (IRI) are risk factors for BK polyomavirus infection after kidney transplantation. However, the mechanism remains unclear. Methods We used a model of mouse polyomavirus (MPyV) infection to investigate the mechanism of IRI and immunosuppressants to promote polyomavirus replication. Results After primary infection, MPyV established persistent infection in the kidneys until week 9 and subsequently were significantly increased by IRI or immunosuppressants treatment individually. In IRI group, viral loads peaked on day 3 in the left kidney, which were significantly higher than that in the right kidney and the control group, and then gradually decreased. In immunosuppressants group, viral loads increased on day 3 without significant difference between left and right kidney, which were significantly higher than that in the control group, and then maintained at high levels. Protein-protein interaction network analysis screened complement C3, EGFR, and FN1 as core genes. Pathway enrichment analysis based on the IRI or immunosuppressants related genes selected by WGCNA indicated that NF-?B signaling pathway was the main pathway involved in promoting MPyV replication. We further confirmed our findings using published datasets GSE47199 and GSE75693. Conclusions Our study demonstrated that IRI and immunosuppressants promote polyomavirus replication through common molecular mechanisms. The mice were randomly divided into 3 groups as follows (1) ischemia-reperfusion injury (IRI) group (N = 20), (2) immunosuppressant (IS) group (N = 20), and (3) control group (N = 20). On 3, 7, 10, 14, and 21 days post-treatment, four mice were randomly sacrificed at each time point, and blood and kidney specimens were collected. Kidney specimens for MPyV-DNA testing were stored at -20C. Kidney tissues from IRI group (day 3, left kidneys N=4, right kidneys N=4, day 7, left kidneys N=4, right kidneys N=4) and IS group (day 3, left kidneys, N=4) were stored in liquid nitrogen for high-throughput RNA sequencing (RNA-seq).