Scientists from the UK have recently identified an antiviral metabolite 3'-Deoxy-3',4'-didehydro-cytidine as a potential serum biomarker to diagnose active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study is currently available on the medRxiv* preprint server while awaiting peer review.
Rapid identification of acute SARS-CoV-2 infection, contact tracing, and patient isolation are the primary control measures to restrict the trajectory of the coronavirus disease 2019 (COVID-19) pandemic. Rapid diagnosis is also vital for timely management of the disease and reduction of morbidity and mortality.
Since the beginning of the pandemic, polymerase chain reaction (PCR)-based identification of SARS-CoV-2 antigen as well as rapid antigen testing are considered to be the gold standard to diagnose COVID-19. In addition, viral cultures are performed for more accurate detection of infectious virus. However, these tests are either expensive and time-consuming or less sensitive to detect active SARS-CoV-2 infection.
In the current study, the scientists have conducted serum metabolite profiling in adult patients who present with a wide variety of infections, including SARS-CoV-2, to identify disease-specific biomarkers.
The study was conducted on patients presented with one of the following health conditions: Gram-positive bacteremia, Gram-negative bacteremia, PCR-confirmed viral infection prior to COVID-19 diagnosis, PCR-confirmed COVID-19, and non-infected inflammatory conditions. In addition, healthy individuals were included as controls. Serum samples from all participants were collected at the time of hospital admission.
For the metabolic profiling, serum samples were collected from a total of 161 patients and 13 healthy controls. The samples were analyzed using high-resolution liquid chromatography coupled with mass spectrometry.
By analyzing the metabolic profiling findings, the scientists observed a significant difference in the abundance of serum metabolites between patients with viral or bacterial infection. Specifically, they identified 3'-Deoxy-3',4'-didehydro-cytidine (ddhC) as a potential serum biomarker for viral infection. According to available literature, ddhC is a free base of the antiviral ribonucleotide ddhC-triphosphate.
With further analysis, the scientists noted that the intensity of ddhC could significantly differentiate viral infection from any other infections analyzed in the study. Specifically, they estimated a 36-fold higher intensity of ddhC in patients with viral infection compared to those with other infections. However, among patients with viral infection, there was no significant difference in ddhC intensity.
To further validate ddhC as a potential diagnostic marker, the scientists compared its sensitivity and specificity with other serum biomarkers, including white blood cell count, lymphocyte count, and C-reactive protein level, which are routinely tested during hospital admission.
The findings revealed that compared to routine clinical markers, ddhC had significantly higher potency in distinguishing viral infection from bacterial and other infections. Specifically, ddhC showed a sensitivity of around 88% and a specificity of around 92%.
To investigate the mechanism of ddhC induction during viral infection, the scientists correlated the ddhC intensity with expression levels of more than 18,000 genes. The findings showed a significant correlation of ddhC intensity with the expressions of two genes, including viperin (virus inhibitory protein) and cytidylate monophosphate kinase 2 (CMPK2), which are interferon-stimulated antiviral genes known to mediate ddhC triphosphate production during viral infection. Moreover, in patients with viral infection, they noticed a significantly high expression of viperin.
The study identifies an antiviral metabolite ddhC as an accurate serum biomarker for a wide range of viral infections, including COVID-19. The metabolite ddhC is a free base of ddhC triphosphate, which is the only identified antiviral small molecule capable of inhibiting viral replication.
The enzyme viperin together with CMPK2, which is immediately adjacent to viperin in the human genome, catalyzes the conversion of cytidine triphosphate to ddhC triphosphate, which acts as a chain terminator for viral RNA-dependent RNA polymerases.
As mentioned by the scientists, the development of an accurate serum diagnostic marker is particularly vital for a pandemic situation like COVID-19, where real-time detection of the infection etiology is necessary to enable rapid isolation of patients and to administer proper therapeutic interventions.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Antiviral metabolite 3'-Deoxy-3',4'-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19 Ravi Mehta, Elena Chekmeneva, Heather Jackson, Caroline Sands, Ewurabena Mills, Dominique Arancon, Ho Kwong Li, Paul Arkell, Timothy Miles Rawson, Robert Hammond, Maisarah Amran, Anna Haber, Graham Cooke, Mahdad Noursadeghi, Myrsini Kaforou, Matthew Lewis, Zoltan Takats, Shiranee Sriskandan, medRxiv, 2021.07.23.21260740; doi: https://doi.org/10.1101/2021.07.23.21260740, https://www.medrxiv.org/content/10.1101/2021.07.23.21260740v1