Chairs: Aoife Mulry and David Mark

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that can cause severe disease and mortality in immunocompromised individuals, including kidney transplant recipients (KTRs). KTRs most at risk from HCMV infection are seronegative recipients (R-) who receive a kidney from an HCMV-infected donor (D+). Some D+R- patients develop HCMV viraemia whilst others do not, and the reasons behind this are poorly understood. In particular, the immunological and metabolic factors that determine HCMV viraemia occurrence are unknown. We performed single-cell RNA sequencing of peripheral blood mononuclear cells from D+R- patients following kidney transplantation, and compared responses in individuals that subsequently developed HCMV viraemia or not. Differential gene expression analysis and an over-representation analysis revealed many differentially regulated key cellular and immunological pathways. D+R- patients that did not develop viraemia displayed immunological differences (e.g., proliferation, cytokines, transcription factors) in NK cells as compared to those that developed viraemia, implying that immunological responses contribute to lack of viraemia in some patients. Furthermore, single-cell flux estimation analysis that characterises cellular metabolism revealed impaired NK cell metabolism in individuals that subsequently developed viraemia. Flow cytometry of histone modifications revealed NK cells prior to the development of viraemia exhibit increased repressive marks compared to those that avoided viraemia. These data suggest that HCMV viraemia occurrence in KTRs may be pre-determined by definable immunological and metabolic parameters, that could help predict HCMV viraemia occurrence and uncover intervention strategies to prevent viraemia in these immunocompromised patients.