Acute and Chronic Changes in Gene Expression After CMV DNAemia in Kidney Transplant Recipients

Abstract

Cytomegalovirus (CMV) viremia continues to cause significant morbidity and mortality in kidney transplant patients with clinical complications including organ rejection and death. Whole blood gene expression dynamics in CMV viremic patients from onset of DNAemia through convalescence has not been well studied to date in humans. To evaluate how CMV infection impacts whole blood leukocyte gene expression over time, we evaluated a matched cohort of 62 kidney transplant recipients with and without CMV DNAemia using blood samples collected at multiple time points during the 12-month period after transplant. While transcriptomic differences were minimal at baseline between DNAemic and non-DNAemic patients, hundreds of genes were differentially expressed at the long-term timepoint, including genes enriching for pathways important for macrophages, interferon, and IL-8 signaling. Amongst patients with CMV DNAemia, the greatest amount of transcriptomic change occurred between baseline and 1-week post-DNAemia, with increase in pathways for interferon signaling and cytotoxic T cell function. Time-course gene set analysis of these differentially expressed genes revealed that most of the enriched pathways had a significant time-trend. While many pathways that were significantly down- or upregulated at 1 week returned to baseline-like levels, we noted that several pathways important in adaptive and innate cell function remained upregulated at the long-term timepoint after resolution of CMV DNAemia. Differential expression analysis and time-course gene set analysis revealed the dynamics of genes and pathways involved in the immune response to CMV DNAemia in kidney transplant patients. Understanding transcriptional changes caused by CMV DNAemia may identify the mechanism behind patient vulnerability to CMV reactivation and increased risk of rejection in transplant recipients and suggest protective strategies to counter the negative immunologic impact of CMV. These findings provide a framework to identify immune correlates for risk assessment and guiding need for extending antiviral prophylaxis.

Transcriptional responses define dysregulated immune activation in Hepatitis C (HCV)-naïve recipients of HCV-infected donor kidneys

“…When the CMV DNAemia cutoff was increased to >137 IU/mL (clinical CMV, n = 9 subjects), the number of upregulated genes increased to 1,187, while 808 genes were downregulated. This included genes involved in immune activation and T cell signaling, including biological processes such as ‘T cell immunoreceptor,’ ‘T cell receptor gamma,’ ‘Fc receptor,’ and ‘lymphocyte activation.’ 335 of those genes overlapped with published CMV response patterns in renal transplant recipients [ 31 ].…”

“…The transcriptomic signals for CMV DNAemia (excluding subclinical infection) and rejection were compared with those from publicly available datasets. For CMV DNAemia, we utilized a case-control study examining longitudinal changes in expression upon the onset of DNAemia, defined as CMV DNA concentrations >137 IU/mL (GEO Accession Number: GSE168598) [ 31 ]. This study from Ahn, et al sampled control patients once and then cases prior to DNAemia and again at three timepoints following DNAemia: 1 week, 1 month, and long-term (approximately 1 year).…”

Plasma Proteome Perturbation for CMV DNAemia in Kidney Transplantation

“…We utilized a previously reported 6 matching transcriptome data on PBMCs collected from the same cohort with matching time points to perform an integrative multi-omic analysis. Data was downloaded from Gene Expression Omnibus (GSE168598), in which there were 153 overlapping time-matching samples present with an overlap of 186 gene/protein present in both transcriptome and proteome datasets.…”

“…We performed a comparative multiome analysis of proteomics data from the plasma samples and transcriptome data available from the matching PBMCs from the same cohort which has been analyzed separately in a previously published paper 6 . Given two different milieus interrogated by transcriptomics (PBMCs) and proteomics (plasma) a significant overlap of target genes/proteins were not expected.…”

“…Furthermore, CMV infection also results in an increased host susceptibility to secondary infections and increased alloimmunity, leading to acute and chronic allograft rejection 3 . Evaluation of peripheral mRNA changes from clinical and sub-clinical CMV primary infection and reactivation has provided insight into causal factors for allograft dysfunction secondary to CMV [4][5][6] , host biological pathways actively altered by the virus 7 , and the dynamic temporal changes of cell cycle, DNA damage molecules [8][9][10][11][12] that occur during the evolution of CMV viral replication 13 . Mass spectrometry-based proteomics of human serum and plasma has been used for identifying markers for disease diagnosis 14 , and for the study of viral infections such as influenza 15 , COVID-19 16,17 , and HIV 18 .…”