The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden; Manipal Institute of Virology (MIV), Manipal Academy of Higher Education, Manipal, India
The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
Emma Kennedy
Public Health England, Porton Down, Salisbury, United Kingdom; Oxford Brookes University, Oxford, United Kingdom
Stuart Dowall
Public Health England, Porton Down, Salisbury, United Kingdom
Binnur K Bagci
Department of Nutrition and Dietetics, Faculty of Health Sciences, Sivas Cumhuriyet University, Sivas, Turkey
Soham Gupta
The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
Jimmy E Rodriguez
Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
Sara Svensson-Akusjärvi
The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
Akhil Banerjea
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
Friedemann Weber
Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany
Roger Hewson
Public Health England, Porton Down, Salisbury, United Kingdom; Oxford Brookes University, Oxford, United Kingdom; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
Ali Mirazimi
Public Health Agency of Sweden, Solna, Sweden; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden; National Veterinary Institute, Uppsala, Sweden
The pathogenesis and host-viral interactions of the Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches, including biological network analysis in elucidating the complex host-viral response, interrogates the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) followed by untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host’s metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and concordant with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at the system level and during progressive replication.
