Multi-omics insights into host-viral response and pathogenesis in CrimeanCongo hemorrhagic fever viruses for novel therapeutic target

Ujjwal Neogi, Nazif Elaldi, Sofia Appelberg, Anoop Ambikan, Emma Kennedy, Stuart Dowall, Binnur K. Bagci, Soham Gupta, Jimmy E. Rodriguez, Sara Svensson-Akusjärvi, Vanessa Monteil, Akos Vegvari, Rui Benfeitas, Akhil Banerjea, Friedemann Weber, Roger Hewson, Ali Mirazimi

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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.

Original languageEnglish
Article numbere76071
JournaleLife
Volume11
DOIs
Publication statusPublished - 19 Apr 2022

Bibliographical note

Funding Information: Vetenskapsrådet (2017-01330) - Ujjwal Neogi. Vetenskapsrådet (2021-00993) - Ujjwal Neogi. Vetenskapsrådet (2018-05766) - Ali Mirazimi. Vetenskapsrådet (2017-03126) - Ali Mirazimi. European Commission (732732) - Roger Hewson. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

The study is funded by Swedish Research Council Grants 2018–05766 and 2017–03126 to AM and 2017–01330 and 2021–00993 to UN, PHE Grant In Aid 109,509 (inc.inc Ph.D. studentship [EK]) and EU-H2020 CCHFVaccine to RH. The plasma and PBMC sample processing part were performed at Sivas Cumhuriyet University Advanced Technology Application and Research Center (CUTAM), Sivas, Turkey, supported by EU-H2020 CCHFVaccine. The authors would like to acknowledge support from the National Genomics Infrastructure (NGI), Science for Life Laboratory, for RNAseq and Proteomics Biomedicum, Karolinska Institute, Solna, for LC-MS/MS analysis. The authors would like to acknowledge Dr. Shubha Krishnan for the critical reading of the manuscript and comment, Maike Sperk, Xi Chen for assisting in some laboratory experiments. The computations were performed using resources provided by SNIC through the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project SNIC2017-550. The microscopy part of the study was performed at the Live Cell Imaging Facility and Biomedicum Imaging Core, Karolinska Institute, Sweden, supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Centre for Innovative Medicine, and the Jonasson Center at the Royal Institute of Technology, Sweden.

Open Access: This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Publisher Copyright: © 2022, Neogi et al.

Citation: Neogi, Ujjwal, et al. "Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target." Elife 11 (2022): e76071.

DOI: 10.7554/eLife.76071

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