Plasma metabolomics profiling for the prediction of cytomegalovirus DNAemia and analysis of virus–host interaction in allogeneic stem cell transplant recipients

Abstract

Metabolomics analysis of biofluids is increasingly being recognized as a useful tool for the diagnosis and management of a number of infectious diseases. Here we showed that plasma metabolomics profiling by untargeted 1 H nuclear magnetic resonance may allow the anticipation of the occurrence of cytomegalovirus (CMV) DNAemia in allogeneic stem cell transplant. For this purpose, key discriminatory metabolites were total glutathione, taurine, methylamine, trimethylamine N-oxide and lactate, all of which were upregulated in patients eventually developing CMV DNAemia. The overall classification accuracy (predictability) of the projection to latent structure discriminant analysis (PLS-DA) model in cross-validation technical replicates was 73 %. Increased levels of alanine, lactate and total fatty acids, and a shift in the fatty acid profile towards unsaturated species, were observed in patients with detectable CMV DNA in plasma. The classification accuracy of this PLS-DA model in cross-validation technical replicates was 81 %. Plasma metabolomics profiling may prove useful for identifying patients at highest risk for CMV DNAemia thus allowing early inception of antiviral therapy.

Metabolic Profiling Early Post-Allogeneic Haematopoietic Cell Transplantation in the Context of CMV Infection

“…We tested the associations of 12 metabolite measures, and only TMAO, which correlated inversely with CMV infection, was found to be associated. This result contradicts the previous findings acquired in the study by Monleón et al 2015 [ 15 ], where higher levels of TMAO were associated with CMV infection in aHSCT patients after transplantation. These differences in results could be due to variations in the studies’ setups (Monleón et al [ 15 ] measured TMAO post-CMV infection onset), the small cohort sizes (59 patients were included in the previous study, and 68 patients were included in our study), or unexplored confounding factors (e.g., haematological malignancy, diet, or other lifestyle-related variables).…”

“…This result contradicts the previous findings acquired in the study by Monleón et al 2015 [ 15 ], where higher levels of TMAO were associated with CMV infection in aHSCT patients after transplantation. These differences in results could be due to variations in the studies’ setups (Monleón et al [ 15 ] measured TMAO post-CMV infection onset), the small cohort sizes (59 patients were included in the previous study, and 68 patients were included in our study), or unexplored confounding factors (e.g., haematological malignancy, diet, or other lifestyle-related variables). TMAO is formed from trimethylamine (TMA), which is produced by the gut microbiota following dietary intake of choline, phosphatidylcholine, and L-carnitine [ 24 , 25 ].…”

“…Furthermore, the pathway annotations performed for the spectrometric data include only one super- and subpathway per molecule and thus do not provide a complete representation of biology, where the same molecule can take part in multiple functions and processes (pleiotropism). Finally, while this study has a larger sample size than previous studies [ 14 , 15 ], power was a limiting factor, particularly with respect to the correlation network analysis, where a large number of correlations were tested. Despite these limitations, we present these results as an explorative investigation of the post-aHSCT metabolic profiles in relation to clinical phenotypes that can be used to generate hypotheses for future studies.…”

“…Several studies have identified metabolites that are potentially relevant for CMV infection. These studies include findings pointing to a glutamine requirement for viral replication [ 13 ] and associations between multiple metabolites and lipids with CMV infection in kidney transplant recipients [ 14 ] and aHSCT recipients [ 15 ]. However, these prior studies were either performed in cell lines or in relatively small clinical cohorts, and their results have not been validated in other cohorts.…”

Disturbance in Plasma Metabolic Profile in Different Types of Human Cytomegalovirus-Induced Liver Injury in Infants

“…However, because of the limitations of the GC-MS platform, VLCFAs were not detected in this study. According to the results of our study and those of previous HCMV-related clinical metabolic studies, although the content of total fatty acid increased, specific fatty acids showed an increasing or decreasing trend 35 . Thus, we hypothesised that HCMV up-regulated specific VLCFAs for incorporation into the viral envelope.…”