Project Details

Early Career

Status: Funded - Open

Mechanisms and Consequences of BK Polyomavirus Infection in Immunocompromised Patients

Anthony Sabulski, MD

Summary

BACKGROUND: Children who undergo hematopoietic stem cell transplant (HSCT) complicated by high BK polyomavirus (BKPyV) viremia (>10,000 copies/mL) have a 70% risk of developing thrombotic microangiopathy (TMA) and nearly half of children who develop BKPyV nephritis after renal transplant lose their graft. This indicates BKPyV causes clinical harm beyond cystitis and nephropathy, and should be treated. Viral specific T-cells (VSTs) effectively treat BKPyV infections and can be safely used after HSCT and solid organ transplant. GAP: Approximately half of pediatric HSCT patients develop BKPyV viremia, yet routine screening for BKPyV is currently not performed at transplant centers due to unclear evidence that BKPyV viremia is harmful and a previous lack of effective therapy. HYPOTHESIS: We hypothesize that BKPyV viremia causes endothelial injury and requires diligent screening and prompt treatment. METHODS: We will perform a prospective longitudinal analysis of circulating endothelial cells (CECs), a non-invasive sample of vascular tissue, in pediatric HSCT patients and define the BKPyV-endothelium interaction using immunofluorescence microscopy (IFM), electron microscopy (EM), and RNAseq of CECs. BKPyV infectivity and the consequences of BKPyV infection of endothelial cells will be further studied using in vitro models of cultured endothelial cells infected with BKPyV from HSCT patients. RESULTS: Our preliminary studies show that CEC elevations correlate with plasma BKPyV copy number and IFM has confirmed intracellular BKPyV in CECs. IMPACT: These findings will support universal screening for BKPyV viremia in pediatric transplant centers and will guide the prophylactic use of VSTs and/or immunomodulating therapies in patients with BKPyV viremia and vascular injury. Website Link: https://www.cincinnatichildrens.org/bio/s/anthony-sabulski