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Integrative molecular structure elucidation and construction of an extended metabolic pathway associated with an ancient innate immune response in COVID-19 patients

We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antivir...

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Main Authors: Sala, Samuele (Author) , Nitschke, Philipp (Author) , Masuda, Reika (Author) , Gray, Nicola (Author) , Lawler, Nathan G. (Author) , Wood, James M. (Author) , Buckler, Joshua N. (Author) , Berezhnoy, Georgy (Author) , Bolaños, Jose (Author) , Boughton, Berin A. (Author) , Lonati, Caterina (Author) , Rössler, Titus (Author) , Singh, Yogesh (Author) , Wilson, Ian D. (Author) , Lodge, Samantha (Author) , Morillon, Aude-Claire (Author) , Loo, Ruey Leng (Author) , Hall, Drew (Author) , Whiley, Luke (Author) , Evans, Gary B. (Author) , Grove, Tyler L. (Author) , Almo, Steven C. (Author) , Harris, Lawrence D. (Author) , Holmes, Elaine (Author) , Merle, Uta (Author) , Trautwein, Christoph (Author) , Nicholson, Jeremy K. (Author) , Wist, Julien (Author)
Format: Article (Journal)
Language:English
Published: February 4, 2024
In: Journal of proteome research
Year: 2024, Volume: 23, Issue: 3, Pages: 956-970
ISSN:1535-3907
DOI:10.1021/acs.jproteome.3c00654
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1021/acs.jproteome.3c00654
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Author Notes:Samuele Sala, Philipp Nitschke, Reika Masuda, Nicola Gray, Nathan G. Lawler, James M. Wood, Joshua N. Buckler, Georgy Berezhnoy, Jose Bolaños, Berin A. Boughton, Caterina Lonati, Titus Rössler, Yogesh Singh, Ian D. Wilson, Samantha Lodge, Aude-Claire Morillon, Ruey Leng Loo, Drew Hall, Luke Whiley, Gary B. Evans, Tyler L. Grove, Steven C. Almo, Lawrence D. Harris, Elaine Holmes, Uta Merle, Christoph Trautwein, Jeremy K. Nicholson, and Julien Wist
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Summary:We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.
Item Description:Gesehen am 16.09.2024
Physical Description:Online Resource
ISSN:1535-3907
DOI:10.1021/acs.jproteome.3c00654

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