BK polyomavirus nephropathy with systemic viral spread: Whole genome sequencing data from a fatal case of BKPyV infection

Abstract

BK polyomavirus (BKPyV) infections with multi-organ involvement are rare. Here, we report for the first time whole genome sequencing data from a patient with systemic BKPyV disease. She presented post stem cell transplantation with graft-vs-host disease, suffered from profound immunosuppression, and developed fatal BKPyV disease of kidneys, lungs, and pancreas. The lytic infection was caused by an episomal BKPyV-Ib strain with canonical structural and receptor encoding gene sequences. However, DNA from all infected tissue sites showed diverse BKPyV-NCCR rearrangements (rr-NCCR) involving the P, Q, and R domains, while largely sparing O and S, carrying initiation sites for early and late BKPyV gene transcripts crucial for viral replication and assembly.Common to all rr-NCCR variants was a break point in Q (position 17-27) that can form the nidus for double DNA strand break formation and gene rearrangements. Metastatic clonal BKPyV spread from kidneys to other organs was not detected. We hypothesize that lack of immune surveillance and a specific NCCR break point promote profound gene rearrangements of NCCR-P, Q, and R with alterations of regulatory feedback loops. As a result, viral replication and pathogenicity are enhanced leading to severe, often fatal systemic disease not caused by the common archetypical BKPyV strains. K E Y W O R D SBK polyomavirus, bone marrow transplantation, genome sequencing, histology, immunohistochemistry, kidney, lung, outcome, pancreas

The 2018 Banff Working Group classification of definitive polyomavirus nephropathy: A multicenter validation study in the modern era

“…PVN is typically caused by intrarenal replication of the BK‐virus (BKPyV) strain and has been associated with graft failure in 30%‐58.3% of patients 2,7 . PVN can also affect native kidneys in severely immunocompromised patients 8,9 …”

Current Status, Prevention and Treatment of BK Virus Nephropathy

“…Unusual manifestations may include vasculopathy, retinitis, hepatitis, systemic lupus erythematosus, Guillain-Barré syndrome, cases of meningoencephalitis and interstitial pneumonitis (24). Metastatic clonal BKV spread from kidneys to other organs was not detected (25).…”

Detection of polyomavirus microRNA-5p expression in saliva shortly after kidney transplantation

“…Among the human polyomavirus-associated diseases, the two major complications associated with BKPyV mainly affect kidney transplant patients (nephropathy) [8][9][10] and allogeneic hematopoietic stem cell transplant patients (hemorrhagic cystitis) [11][12][13], only sporadically occurring in patients with other solid organ transplantation or other immune deficiencies [14][15][16]. Although the mechanism underlying the reactivation of polyomaviruses is not yet well known, it seems that variations in their non-coding control region (NCCR) are associated with high viral replication activity, which is implicated in the development of polyomavirus-associated diseases [2,17].…”