Abstract
Introduction: BK polyomavirus (BKV) infection is associated with injury and subsequent graft loss due to the extent of injury or rejection. However, the molecular mechanisms driving injury and subsequent adverse outcomes remain poorly understood. Methods: In a cross-sectional study, single-cell RNA sequencing from kidney allograft biopsies was used to assess cell type-specific responses between uninfected controls and two distinct phases of BKV infection: peaking (increasing viral blood titers) and resolving (decreasing viral titers following immunosuppression reduction). Results: Genes upregulated in BK viral nephropathy (BKVN) were enriched for polyomavirus infection hallmarks, including ribosome biogenesis, translation, and energy restructuring. Additionally enriched pathways included wound healing, cellular stress, antigen presentation and immune signaling. Even without BKVN (peaking BK viremia alone), epithelial cells expressed signatures for wound healing, cellular stress, and extracellular matrix remodeling. In vivo tubular cell responses at single-cell resolution were validated against single cell transcriptomic data of BKV infected cells in a cell culture model. Despite similarities, in vivo tubular cells underwent metabolic adaptation favoring fatty acid oxidation and proinflammatory responses not observed in culture models likely due to an absent innate and adaptive immune system. Despite lymphopenia and immunosuppressive therapies, the proportion of recipient derived intrarenal adaptive immune cells was increased in biopsies associated with peaking viremia alongside activation of innate immune responses. Adaptive immune cells exhibited persistent inflammatory signaling and remodeling of energy metabolism during the resolving phase of infection. Conclusion: These not previously reported insights into BKV-associated injury may have implications for clinical management and improved allograft outcomes.
Authors
Tess Marvin, Rachel Sealfon, Phillip J. McCown, Fadhl AlAkwaa, Evan A. Farkash, Edgar A. Otto, Felix Eichinger, Ping An, Rajasree Menon, Celine C. Berthier, Tavis J. Reed, Paula Arrowsmith, Lalita Subramanian, Kelly J. Shaffer, Silas P. Norman, Ramnika Gumber, Michael J. Imperiale, James M. Pipas, Olga G. Troyanskaya, Matthias Kretzler, Chandra L. Theesfeld, Abhijit S. Naik
