Antiviral metabolite 3′-deoxy-3′,4′-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19

Abstract

Background There is a critical need for rapid viral infection diagnostics to enable prompt case identification in pandemic settings and support targeted antimicrobial prescribing. Methods Using untargeted high-resolution liquid chromatography coupled with mass spectrometry, we compared the admission serum metabolome of emergency department patients with viral infections including COVID-19, bacterial infections, inflammatory conditions, and healthy controls. Sera from an independent cohort of emergency department patients admitted with viral or bacterial infections underwent profiling to validate findings. Associations between whole-blood gene expression and the identified metabolite of interest were examined. Findings. 3'-Deoxy-3',4'-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), was detected for the first time in serum. When comparing 60 viral to 101 non-viral cases in the discovery cohort, ddhC was the most differentially abundant metabolite, generating an area under the receiver operating characteristic curve (AUC) of 0.954 (95% CI: 0.923-0.986). In the validation cohort, ddhC was again the most significantly differentially abundant metabolite when comparing 40 viral to 40 bacterial cases, generating an AUC of 0.81 (95% CI 0.708-0.915). Transcripts of viperin and CMPK2 , enzymes responsible for ddhCTP synthesis, were amongst the five genes most highly correlated to ddhC abundance. Conclusions The antiviral precursor molecule ddhC is detectable in serum and an accurate marker for acute viral infection. Interferon-inducible genes viperin and CMPK2 are implicated in ddhC production in vivo . These findings highlight a future diagnostic role for ddhC in viral diagnosis, pandemic preparedness, and acute infection management.

Quantitative LC-MS study of compounds found predictive of COVID-19 severity and outcome

“…Elevated but non-quantitated serum levels of ddhC in COVID-19 patients have been previously reported by Mehta et al (Mehta et al, 2022). Comparable to our results, ddhC showed exceptionally good capacity at distinguishing infected individuals from controls but its relation to disease severity was not so obvious.…”

“…Comparable to our results, ddhC showed exceptionally good capacity at distinguishing infected individuals from controls but its relation to disease severity was not so obvious. In the study performed by Mehta et al (Mehta et al, 2022) ddhC was correlated with COVID-19 severity in the discovery cohort but not their validation cohort. In our data we found that the highest levels of ddhC in intermediate COVID-19 severity subgoup.…”

Metabolite, protein, and tissue dysfunction associated with COVID-19 disease severity

“…Host response to infection can be measured by profiling small molecules (metabolites) and large molecules (proteins). For example, 3′-Deoxy-3′,4′-didehydro-cytidine (ddhC), a human antiviral metabolite, was significantly increased in COVID-19 patients 10 , and Gamma aminobutyric acid (GABA) metabolite was suggested as a potential signaling molecule by activating B cells and plasma cells 11 . We aimed to investigate metabolite and protein profiles to develop a comprehensive snapshot of host response and identify potential molecular biomarkers associated with COVID-19 disease severity.…”

Quantitative LC-MS study of compounds found predictive of COVID-19 severity and outcome

“…In the study performed by Mehta et al . (Mehta et al, 2022) ddhC was correlated with COVID-19 severity in the discovery cohort but not their validation cohort. In our data we found that the highest levels of ddhC in intermediate COVID-19 severity subgoup.…”