Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus

Abstract

Background: Acute infectious diseases are typically accompanied by non-specific symptoms including fever, malaise, irritability and somnolence that usually resolve on recovery. However, in some individuals these symptoms persist in what is commonly termed post-infective fatigue. The objective of this pilot study was to determine the gene expression correlates of post-infective fatigue following acute Epstein Barr virus (EBV) infection.

Methods: We followed 5 people with acute mononucleosis who developed post-infective fatigue of more than 6 months duration and 5 HLA-matched control subjects who recovered within 3 months. Subjects had peripheral blood mononuclear cell (PBMC) samples collected at varying time points including at diagnosis, then every 2 weeks for 3 months, then every 3 months for a year. Total RNA was extracted from the PBMC samples and hybridized to microarrays spotted with 3,800 oligonucleotides.

Results: Those who developed post-infective fatigue had gene expression profiles indicative of an altered host response during acute mononucleosis compared to those who recovered uneventfully. Several genes including ISG20 (interferon stimulated gene), DNAJB2 (DnaJ [Hsp40] homolog and CD99), CDK8 (cyclin-dependent kinase 8), E2F2 (E2F transcription factor 2), CDK8 (cyclin-dependent kinase 8), and ACTN2 (actinin, alpha 2), known to be regulated during EBV infection, were differentially expressed in post-infective fatigue cases. Several of the differentially expressed genes affect mitochondrial functions including fatty acid metabolism and the cell cycle.

Conclusion: These preliminary data provide insights into alterations in gene transcripts associated with the varied clinical outcomes from acute infectious mononucleosis.

Figure 1

There were 23 of 636 genes that were expressed at different levels between cases (blue bars) and controls (orange bars) at the early time point. The majority of these (15/23) were expressed at higher levels in the cases compared to controls and most were involved in cell cycle and metabolism. The four genes known to be involved in translation, were expressed at much lower levels in the cases compared to controls.

Figure 2

Comparison of genes that were expressed at similar levels during early and late time points for cases (blue bars) but were different for controls (orange bars). There were 24 of 636 genes that were differentially expressed. Half of these genes have known mitochondrial function and are marked with an asterisk.

Figure 3

Cluster analysis of 24 differentially expressed genes of all samples from cases and controls at both early and late time points. The samples separated into 2 major groups; one containing most of the case samples and the other containing both cases and controls. The genes also grouped into 2 major groups; one that contained most of the mitochondrial function genes that were upregulated in cases and the other contained cell cycle checkpoints and DNA replication genes that were down regulated in the case group.