Aim: In immunocompetent individuals, Cytomegalovirus (CMV) causes mostly asymptomatic but lifelong infection. However, in immunocompromised kidney transplant recipients (KTx), CMV infection can increase morbidity and mortality, and decrease graft survival. Despite antiviral prophylaxis, CMV viremia is common post-transplant and has long-lasting effects on the immune system, with the highest risk for infection and downstream sequelae in CMV naïve recipients paired with CMV latently infected donors. We sought to improve understanding of the longitudinal dynamics of CMV infection in KTx to aid prevention and control efforts.
Methods: We performed multi-omic immune profiling of 31 KTx prior to (“Pre-viremia”) and acutely post-CMV viremia (“Post-viremia”), as well as 31 matched KTx controls who did not experience CMV viremia (“CMV-“). Multi-omic profiling included peripheral blood methylation, transcriptomics, plasma analytes, immune cell phenotypes, and CMV-specific immunity to identify host immune signatures of CMV viremia. Key findings were validated in an independent cohort of 177 KTx with and without CMV viremia.
Results: At one week post detection of CMV viremia (Fig. 1A-F), we observed increased production of inflammatory cytokines, interferon signaling, and increased frequency of CD8 T cells, particularly memory cells. Notably, prior to detection of CMV viremia by PCR (Fig. 1G-I), many of these same pathways were already upregulated. Even more strikingly, plasma IL-15 and IL-2 were significantly elevated exclusively pre-viremia (Fig. 1J). The relationship between IL-2 and CMV viremia was validated in an independent KTx cohort (Fig. 1K), showing potential as an early predictor of viremia, particularly in KTx with primary infection (Fig. 1L, “CMV R-“).
Conclusion: Identified multi-omic signatures highlighted the dynamics of cytokine production and T cell signaling around CMV viremia, and their potential to sense CMV primary infection and/or reactivation prior to detection of viral DNA in the periphery. Most notably, plasma IL-2 showed potential as an early indicator of CMV replication, prior to CMV being detectable in blood, particularly in the context of primary infection. The ability to detect risk for CMV replication prior to detection by CMV PCR has important clinical applications for patient risk stratification and timing of antiviral prophylaxis.
