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Study unveils previously unknown urinary biomarkers, revolutionizing early detection and treatment of viral infections like COVID-19
Aug
In a recent study posted to the medRxiv preprint* server, a global team of researchers evaluated metabolic responses to acute coronavirus disease 2019 (COVID-19) and identified biomarkers for acute viral infections.
Study: SARS-CoV-2 Infection Biomarkers Reveal an Prolonged RSAD2 Dependant Metabolic Pathway. Image Credit: NIAID
*Vital notice: medRxiv publishes preliminary scientific reports that aren’t peer-reviewed and, due to this fact, mustn’t be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
The COVID-19 pandemic has caused unprecedented morbidity and mortality globally. Effective therapeutics and tools for early detection and prompt treatment should be developed to mitigate disease. Research is required to enhance our understanding of the biological characteristics of the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
COVID-19 is characterised by pulmonary and extrapulmonary symptoms with complex pathophysiological and immunological effects on major organs. The combined metabolic disruption and immunological stimulation in COVID-19 patients can result in persistent symptoms and the event of post-acute coronavirus disease 2019 syndrome (PACS) or long-COVID.
Serological biomarkers corresponding to ferritin, C-reactive protein (CRP), and lactate dehydrogenase (LDH) have been identified to trace the event and recovery from COVID-19. As well as, altered levels of serological and urinary lipids, amino acids, lipoproteins, cytokines, and tryptophan metabolites have been observed amongst COVID-19 patients.
Concerning the study
In the current study, researchers elucidated candidate COVID-19 biomarkers by performing a spectroscopic evaluation.
Two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry were used to characterize and quantify metabolites with potential diagnostic value for viral diseases in urine. The correlation between the urinary nucleoside analogs and serological cytokines, corresponding to interleukin-10 (IL-10), interferon-alpha2 (IFN-α2), and interferon-gamma (IFN-γ) was investigated to find out the connection between the virus inhibitory protein, endoplasmic reticulum-associated and interferon-inducible (viperin) enzyme [or radical S-Adenosyl methionine domain-containing 2 (RSAD2)] and the endogenous protective innate immunological responses against viruses corresponding to SARS-COV-2.
Specifically, the team investigated whether the antiviral deoxy-didehydronucleosides (ddhN) were measurable within the urinary samples and evaluated their role as a biomarker. A family of endogenous cytosine metabolites with potential antiviral activity was biosynthesized in vivo during SARS-CoV-2 replication. The team modeled urine spectral data from 273 SARS-CoV-2-infected individuals and 77 non-infected individuals (controls) using principal component evaluation (PCA) and OPLS-DA. COVID-19 patients were recruited between July 2022 and January 2023 in ambulatory settings within the urban areas of Heidelberg.
To evaluate COVID-19 severity and its impact on the excretion of ddhN metabolites, the group of COVID-19 patients was subdivided into non-hospitalized and hospitalized individuals. The team investigated the excretion profiles of nucleosides within the initial week of SARS-CoV-2 infection amongst six COVID-19 patients who were diagnosed using polymerase chain response (PCR) or rapid antigen tests (RAT). Flow cytometry was performed to quantify serological cytokines. Linear regression modeling was performed to find out associations between the ddhN metabolites.
Results
The study analyzed urine from acute COVID-19 patients, revealing a spectroscopic signature related to anomeric CH-1′ ddhN protons. Nuclear magnetic resonance spectroscopy showed a definite spin-system motif, which indicated that several metabolites were present in urine through the acute SARS-CoV-2 proliferation.
Mass spectrometry revealed essentially the most abundant serological metabolites with diagnostic potential for viral diseases. The findings revealed an prolonged innate viperin-dependent pathway contributing to an adaptive response to viral agents like SARS-CoV-2. In total, 10 nucleoside analogs (uracil- and cytosine-based) were identified, of which eight haven’t been reported previously in humans, indicating more evolutionary and metabolic adaptability to viral infections than previously believed.
The evaluation also revealed a correlation between the urinary analogs and viperin enzyme-related serological cytokines. The detection of ddhNs in serum was related to inflammation, with the mean concentration of the three most abundant nucleosides being a minimum of 1 order of magnitude greater amongst individuals infected with SARS-CoV-2 in comparison with controls.
The foremost urinary ddhN metabolites accurately distinguished SARS-CoV-2-infected individuals from controls and showed strong correlations with serological interferon-alpha2 and interferon-gamma levels, with weaker correlations with IL-10, 17, and 18. Interferon-alpha is raised in COVID-19 and is linked to a rise within the variety of T cell subsets implicated in initial responses to viruses. Interferon-alpha and interleukin-10 are linked to lung damage, predict COVID-19 severity, and were present in greater amounts in symptomatic individuals.
Time trajectories indicated rapid ddhN clearance from the body through urine. The structural similarities between the nucleosides and their antiviral equivalents, which have transient half-lives in humans, indicated that a decrease in levels over time for the endogenous antivirals could indicate the recent introduction of short-term enzyme activity induced by immunological stimuli.
Overall, the study findings highlighted the presence of an prolonged RSAD2-dependent metabolic pathway which will contribute to an endogenous innate immunological defense mechanism against viral infections corresponding to COVID-19. Measurement of the excretion of ddhN metabolites could also be used reliably as a direct indication of viral infection and potential severity. The observed biomarkers may prove priceless in developing tools for early detection and monitoring of viral infections and should lead to clinical actionability concerning acutely unwell patients.
*Vital notice: medRxiv publishes preliminary scientific reports that aren’t peer-reviewed and, due to this fact, mustn’t be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.
