CMV Plasma Proteomics in Kidney Transplant

Background. Cytomegalovirus (CMV) infection, either de novo or a reactivation infection, is recognized to result in detrimental alloimmune effects, inclusive of higher susceptibility to graft rejection and opportunistic infections and a substantive impact on chronic graft injury and reduced transplant survival. We studied perturbations in the circulating host proteome serially, before and after transplantation, and during and after CMV DNA replication (DNAemia), as measured by quantitative polymerase chain reaction (QPCR), to obtain further insights into the evolution and pathogenesis of CMV infection in an immunocompromised host. Method. LC-MS-based proteomics was conducted on 168 serially banked plasma samples, at protocol times of 3- and 12-months post-transplant, before and 1 week and 1 month after detection of CMV DNAemia. Sixty-two propensity score-matched kidney transplant recipients were enrolled, stratified by CMV replication status into 31 with CMV DNAemia and 31 without CMV DNAemia. Plasma proteins were analyzed using an LCMS 8060 triple quadrupole mass spectrometer. Differential expression analysis was conducted using R and Limma. An integrative analysis with transcriptome data on matching PBMCs was also carried out. Result. Samples were segregated based on their proteomic profiles with respect to their CMV Dnaemia status. A subset of 17 plasma proteins was observed to predict the onset of CMV at 3 months post-transplant enriching platelet degranulation (FDR, 4.83E-06), acute inflammatory response (FDR, 0.0018), blood coagulation (FDR, 0.0018) pathways. Analysis of plasma proteome comparing patients with and without DNAemia revealed an increase in the immune complex proteins and immune-related protein as a response to CMV infection. Compared to pre-DNAemia plasma proteome, post-DNAemia timepoint plasma proteome revealed increased protein levels of proteins such as anti-inflammatory adipokine vaspin (SERPINA12), copper binding protein ceruloplasmin (CP), complement activating protein CFH enriching immune processes such as complement activation (FDR=0.03), Humoral immune response (FDR=0.01), innate immune response (FDR=0.01). Conclusion. High throughput plasma proteomics revealed proteomic perturbation impacting immune system-associated pathways during CMV infection and provided insights into biomarkers for CMV disease prediction and resolution. Further studies to understand the clinical impact of these pathways in formulating different types and duration of anti-viral therapies in the immunocompromised host.