Abstract
The mosquito-borne Usutu virus (USUV) is a zoonotic flavivirus and an emerging pathogen. So far therapeutical options or vaccines are not available in human and veterinary medicine. The bioenergetic profile based on extracellular flux analysis revealed an USUV infection-associated significant increase in basal and stressed glycolysis on Vero and with a tendency for basal glycolysis on the avian cell line TME-R derived from Eurasian blackbirds. On both cell lines this was accompanied by a significant drop in the metabolic potential of glycolysis. Moreover, glycolysis contributed to production of virus progeny, as inhibition of glycolysis with 2-deoxy-D-glucose reduced virus yield on Vero by one log10 step. Additionally, the increase in glycolysis observed on Vero cells after USUV infection was lost after the addition of exogenous type I interferon (IFN) β. To further explore the contribution of the IFN response pathway to the impact of USUV on cellular metabolism, USUV infection was characterized on human A549 respiratory cells with a knockout of the type I IFN receptor, either solely or together with the receptor of type III IFN. Notably, only the double knockout of types I and III IFN receptor increased permissiveness to USUV and supported viral replication together with an alteration of the glycolytic activity, namely an increase in basal glycolysis to an extent that a further increase after injection of metabolic stressors during extracellular flux analysis was not noted. This study provides evidence for glycolysis as a possible target for therapeutic intervention of USUV replication. Moreover, presented data highlight type I and type III IFN system as a determinant for human host cell permissiveness and for the infection-associated impact on glycolysis.
Highlights
The mosquito-borne Usutu virus (USUV) is an emerging zoonotic flavivirus (Simmonds et al, 2017) and within the family Flaviviridae it belongs to the Japanese encephalitis virus serogroup together with West Nile virus (WNV)
At 96 hpi a cytopathic effect (CPE) was induced by both multiplicity of infection (MOI), which results in alterations of the Vero cell monolayer (Supplement Figure 1A)
Already at 24 h postinfection almost all cells were infected at MOI 1 and at 48 hpi no difference in the rate of USUV-positive cells was notable between MOI 0.1 and 1
Summary
The mosquito-borne Usutu virus (USUV) is an emerging zoonotic flavivirus (Simmonds et al, 2017) and within the family Flaviviridae it belongs to the Japanese encephalitis virus serogroup together with West Nile virus (WNV). Based on phylogenetic analysis this enveloped virus with a single-stranded RNA genome in positive polarity (Simmonds et al, 2017) is arranged in eight lineages, three African (Africa 1 to 3) and five European (Europe 1 to 5) (Cadar et al, 2017; Vilibic-Cavlek et al, 2020). Despite its high mortality rate in some avian species, in most cases USUV infection in humans is asymptomatic (Benzarti and Garigliany, 2020). Comparable to encephalitis cases noted for other flaviviruses, neuroinvasion together with the occurrence of neurological symptoms are reported after USUV infection in immunocompromised and even in immunocompetent patients (Pecorari et al, 2009; Grottola et al, 2017; Simonin et al, 2018; Nagy et al, 2019; Zelena et al, 2021)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
