Non-Permissive Human Conventional Cd1c(+) Dendritic Cells Enable Trans-Infection Of Human Primary Renal Tubular Epithelial Cells And Protect Bk Polyomavirus From Neutralization

The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney transplant recipients (KTRs) and hematopoietic stem cell transplant recipients. In KTRs, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDCs) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived dendritic cells (MDDCs), an in vitro model for mDCs, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDCs. Endocytosed virions were efficiently transmitted to permissive cells and protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c(+) mDCs from the blood and kidney parenchyma behaved similarly to MDDCs thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c(+) mDC involvement in the BKPyV infection as a promoter of viral spreading.Author summaryDr Sylvia Gardner first discovered the BK polyomavirus (BKPyV) in the urine of a kidney-transplant recipient in 1970. In the 1990's, the widespread use of potent immunosuppressive drugs such as tacrolimus, sirolimus or mycophenolate mofetil led to the emergence of BKPyV nephropathy. Recently, various studies reported a specific influx of myeloid dendritic cells (mDCs) in the renal tissue of kidney-transplant patients who were diagnosed with a BKPyV nephropathy. MDCs are immune cells both residing in tissues and migrating to other organs or compartments like the blood when changes in their environment occur. Their main functions are the detection of danger signals such as pathogens or tumors and the processing of antigens to prime naive specific effectors of the adaptive immune response. Although anti-BKPyV cellular immune responses have been investigated in post-transplant recipients as well as healthy individuals, supporting an active role of mDCs little is known about how mDCs and BKPyV interact with each other. Our study provides the basis to understand the role played by mDCs in virus capture through an unprecedented endocytic mechanism and possibly in viral protection from neutralization by specific antibodies. Moreover, we showed that mDCs are unable to sense BKPyV particles or BKPyV-infected dying cells as a danger signal, supporting the view that other DC subsets might act as the true antigen presenting cells that promote the adaptive immune response against BKPyV infection.