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Publication Detail
Antiviral metabolite 3'-Deoxy-3',4'-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19
  • Publication Type:
    Journal article
  • Authors:
    Mehta R, Chekmeneva E, Jackson H, Sands C, Mills E, Arancon D, Li HK, Arkell P, Rawson TM, Hammond R, Amran M, Haber A, Cooke G, Noursadeghi M, Kaforou M, Lewis MR, Takats Z, Sriskandan S
  • Publisher:
    Elsevier BV
  • Publication date:
    31/01/2022
  • Journal:
    Med
  • Medium:
    Print-Electronic
  • Status:
    Published
  • Country:
    United States
  • PII:
    S2666-6340(22)00044-7
  • Language:
    English
  • Keywords:
    COVID-19, antiviral, bacterial, biomarker, ddhC, mass spectrometry, metabolomics, serum, viral
  • Notes:
    This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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.
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