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Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target.
Neogi, Ujjwal; Elaldi, Nazif; Appelberg, Sofia; Ambikan, Anoop; Kennedy, Emma; Dowall, Stuart; Bagci, Binnur K; Gupta, Soham; Rodriguez, Jimmy E; Svensson-Akusjärvi, Sara; Monteil, Vanessa; Vegvari, Akos; Benfeitas, Rui; Banerjea, Akhil; Weber, Friedemann; Hewson, Roger; Mirazimi, Ali.
  • Neogi U; The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden.
  • Elaldi N; Manipal Institute of Virology (MIV), Manipal Academy of Higher Education, Manipal, India.
  • Appelberg S; Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Cumhuriyet University, Sivas, Turkey.
  • Ambikan A; Public Health Agency of Sweden, Solna, Sweden.
  • Kennedy E; The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden.
  • Dowall S; Public Health England, Porton Down, Salisbury, United Kingdom.
  • Bagci BK; Oxford Brookes University, Oxford, United Kingdom.
  • Gupta S; Public Health England, Porton Down, Salisbury, United Kingdom.
  • Rodriguez JE; Department of Nutrition and Dietetics, Faculty of Health Sciences, Sivas Cumhuriyet University, Sivas, Turkey.
  • Svensson-Akusjärvi S; The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden.
  • Monteil V; Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Vegvari A; The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden.
  • Benfeitas R; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden.
  • Banerjea A; Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  • Weber F; National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  • Hewson R; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
  • Mirazimi A; Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen, Germany.
Elife ; 112022 04 19.
Article in English | MEDLINE | ID: covidwho-1791920
ABSTRACT
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.
Crimean-Congo hemorrhagic fever (CCHF) is an emerging disease that is increasingly spreading to new populations. The condition is now endemic in almost 30 countries in sub-Saharan Africa, South-Eastern Europe, the Middle East and Central Asia. CCHF is caused by a tick-borne virus and can cause uncontrolled bleeding. It has a mortality rate of up to 40%, and there are currently no vaccines or effective treatments available. All viruses depend entirely on their hosts for reproduction, and they achieve this through hijacking the molecular machinery of the cells they infect. However, little is known about how the CCHF virus does this and how the cells respond. To understand more about the relationship between the cell's metabolism and viral replication, Neogi, Elaldi et al. studied immune cells taken from patients during an infection and one year later. The gene activity of the cells showed that the virus prefers to hijack processes known as central carbon and energy metabolism. These are the main regulator of the cellular energy supply and the production of essential chemicals. By using cancer drugs to block these key pathways, Neogi, Elaldi et al. could reduce the viral reproduction in laboratory cells. These findings provide a clearer understanding of how the CCHF virus replicates inside human cells. By interfering with these processes, researchers could develop new antiviral strategies to treat the disease. One of the cancer drugs tested in cells, 2-DG, has been approved for emergency use against COVID-19 in some countries. Neogi, Elaldi et al. are now studying this further in animals with the hope of reaching clinical trials in the future.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hemorrhagic Fever Virus, Crimean-Congo / Hemorrhagic Fever, Crimean Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: ELife.76071

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hemorrhagic Fever Virus, Crimean-Congo / Hemorrhagic Fever, Crimean Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: ELife.76071