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Published May 8, 2023 | Version v1
Journal article Open

SARS-CoV-2 Infection Biomarkers Reveal Adaptive Evolutionary Chemistry of Antiviral Nucleoside Metabolism

Creators

  • 1. The Australian National Phenome Centre and Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, Australia, WA6150
  • 2. Ferrier Research Institute, Victoria University of Wellington, Wellington 6012, New Zealand ;The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
  • 3. Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, University Hospital Tuebingen, Tuebingen, Germany
  • 4. Chemistry Department, Universidad del Valle, Cali 76001, Colombia
  • 5. Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Germany
  • 6. Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College, Burlington Danes Building, Du Cane Road, London W12 0NN, UK
  • 7. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, United States
  • 8. The Australian National Phenome Centre and Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, Australia, WA6150 ;Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College, Burlington Danes Building, Du Cane Road, London W12 0NN, UK
  • 9. Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
  • 10. The Australian National Phenome Centre and Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, Australia, WA6150 ;Institute of Global Health Innovation, Faculty of Medicine, Imperial College London, Level 1, Faculty Building, South Kensington Campus, London, SW7 2NA, UK
  • 11. The Australian National Phenome Centre and Computational and Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Building, Perth, Australia, WA6150 ;Chemistry Department, Universidad del Valle, Cali 76001, Colombia

Description

We present compelling evidence for the existence of an evolutionary adaptive response to viral agents such as SARS-CoV-2, that results in the human in vivo biosynthesis of a family of compounds with potential antiviral activity. Using nuclear magnetic resonance (NMR) spectroscopy, we detected a characteristic spin-system motif indicative of the presence of an extended panel of urinary and serum metabolites during the acute viral phase. The structure of eight of nucleoside analogues was elucidated (six of which have not previously been reported in human urine), and subsequently confirmed by total-synthesis and matrix spiking. 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 endogenous innate immune defense mechanism against viral infection.

Notes

Acknowledgements: Acknowledgements: We thank The Spinnaker Health Research Foundation, WA, The McCusker Foundation, WA, The Western Australian State Government and the Medical Research Future Fund (EPCD000037 and MRF2014349) for financial support. We thank the Department of Jobs, Tourism, Science and Innovation, Government of a Western Australian Premier's Fellowship for RLL and the ARC for Laureate Fellowship funding for EH. JW thanks Ministerio de Ciencia, Tecnología e Innovación (Minciencias), Ministerio de Educación Nacional, Ministerio de Industria, Comercio y Turismo e ICETEX (792–2017) 2a Convocatoria Ecosistema Científico - Colombia Científica para la Financiación de Proyectos de I + D + i), World Bank and Vicerrectoría de Investigaciones, Pontificia Universidad Javeriana, Bogotá, Colombia (contract no. FP44842 - 221-2018). We gratefully thank the Werner Siemens Imaging Center under direction of Prof. Bernd Pichler for supporting this project as well as Aditi Kulkarni and Daniele Bucci for excellent technical assistance. JMW, GBE and LDH thank the New Zealand Ministry of Business Innovation & Employment for support (Endeavour Fund program contract UOOX1904 (NZ)).

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