TRPC6, a Novel Target for BK Infection

Background: BK polyomavirus-associated nephropathy (BKPyVAN) affects 3–5% of the 25,000 annual U.S. kidney transplant recipients, causing >50% graft loss and a $5 billion burden (CDC, 2025). Reducing immunosuppression risks rejection, highlighting the need for targeted antivirals. Tacrolimus worsens BKPyV infection vs. cyclosporine, but mechanisms are unclear. JC polyomavirus uses 5-HT2a receptor and TRPC6 for entry. We hypothesize tacrolimus enhances TRPC6 activity, promoting BKPyV endocytosis via calcium influx and caveolin-1 stabilization similar to JCPyV. This project targets TRPC6 to reduce graft loss and inform polyomavirus prophylaxis. Methods: Cell culture, electrophysiology, calcium imaging and database analysis were employed to investigate the effect of tacrolimus mediated BKPyV excarbation. Results: TriNetX analysis (n=37,537) showed tacrolimus increased BKPyV risk vs. cyclosporine in kidney transplant recipients. Tacrolimus (n=20,099) had 7.6% prevalence and 16.7% incidence; cyclosporine (n=2,562) had 3.8% prevalence and 13.0% incidence (p<0.0001). Other viral infections were higher with tacrolimus (17.4%, 28.71%) vs. cyclosporine (73.3%, 15.0%) (p<0.0001). No calcineurin inhibitors (n=5,676) had the lowest BKPyV rates (17.0%, 5.8%). Conclusion: Targeting TRPC6 may reduce BKPyV infection and graft loss in kidney transplant recipients.Prevalence and cumulative incidence of BKPyV with tacrolimus and cyclosporine - Immunosuppresive regimen Cohort Size Kidney Transplant Infection (BKPyV) Other viral agents Tacrolimus 20,099 Prevalence: 7.6% (1228/20,099) Cum. Incidence: 16.7% (no CI)Prevalence: p < 0.0001 Cum. Incidence: p < 0.0001 Prevalence: 17.4% (5088/20,099) Cum. Incidence: 28.71% (no CI)Prevalence: p < 0.0001 Cum. Incidence: p < 0.0001 Cyclosporine 2,562 Prevalence: 3.8% (38/562) Cum. Incidence: 13.0% (95% CI: 7.8–18.0)Prevalence: p < 0.0001 Cum. Incidence: p < 0.0001 Prevalence: 73.3% Cum. Incidence: 15.0% (95% CI: 13.8–16.0)Prevalence: p < 0.0001 Cum. Incidence: p > 0.0055 No Calcineurin Inhibitors 5,676 Prevalence: 17.0% (105/676) Cum. Incidence: 5.8% (95% CI: 3.8–7.4)Prevalence: p < 0.0001 Cum. Incidence: p < 0.0001 Prevalence: 5.37% Cum. Incidence: 14.0% (95% CI: 11.8–21.77)Prevalence: p < 0.0001 Cum. Incidence: p > 0.0055