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

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.

Role of myeloid cells in system-level immunometabolic dysregulation during prolonged successful HIV-1 treatment

“…Viral infections hijack the cellular metabolic environment, mostly AAs, CCM, and sugars, for their support and propagation [ 11 , 16 , 17 ]. As the significant systemic alteration of the metabolites was glucose, pyruvate/lactate, and glutamate, next we performed flow cytometry analysis of metabolite transporters, glucose transporter-1 (Glut1), pyruvate and lactate transporter monocarboxylate transporter 1 (MCT-1), and cysteine/glutamate antiporter (xCT) in a cohort of HC ( n = 9) and PWH ART ( n = 27) (Fig.…”

The Relationship between DUGBE Virus Infection and Autophagy in Epithelial Cells

“…This was in contrast to CCHFV infection, for which we could not detect an impact of core autophagy gene engagement on virion production. Whether the marked endoplasmic reticulum (ER)-stress response [ 31 ] and hijacking of carbon and energy metabolism [ 42 ] that were uncovered in CCHFV-infected cells are also taking place in DUGV-infected cells and whether they impact the anti-viral autophagy of epithelial cells remain to be studied. In a comparative analysis of primary human antigen presenting cells (dendritic cells and macrophages derived from blood progenitors), DUGV was found to induce higher levels of cytokine and chemokine production (interleukin-6, RANTES, IP-10, and MIP-1α) than CCHFV, especially in the case of macrophages [ 30 ].…”

Lactate is useful for the efficient replication of porcine epidemic diarrhea virus in cell culture

“…Previous studies have shown that viruses alter the metabolism of host cells in order to provide optimal conditions for rapid and efficient reproduction and transmission ( 9 – 12 ). Viruses rely on the host cell machinery for reproduction.…”