Glycolytic shift during West Nile virus infection provides new therapeutic opportunities

Abstract

Background Viral rewiring of host bioenergetics and immunometabolism may provide novel targets for therapeutic interventions against viral infections. Here, we have explored the effect on bioenergetics during the infection with the mosquito-borne flavivirus West Nile virus (WNV), a medically relevant neurotropic pathogen causing outbreaks of meningitis and encephalitis worldwide. Results A systematic literature search and meta-analysis pointed to a misbalance of glucose homeostasis in the central nervous system of WNV patients. Real-time bioenergetic analyses confirmed upregulation of aerobic glycolysis and a reduction of mitochondrial oxidative phosphorylation during viral replication in cultured cells. Transcriptomics analyses in neural tissues from experimentally infected mice unveiled a glycolytic shift including the upregulation of hexokinases 2 and 3 (Hk2 and Hk3) and pyruvate dehydrogenase kinase 4 (Pdk4). Treatment of infected mice with the Hk inhibitor, 2-deoxy-D-glucose, or the Pdk4 inhibitor, dichloroacetate, alleviated WNV-induced neuroinflammation. Conclusions These results highlight the importance of host energetic metabolism and specifically glycolysis in WNV infection in vivo. This study provides proof of concept for the druggability of the glycolytic pathway for the future development of therapies to combat WNV pathology.

The Antiviral Potential of AdipoRon, an Adiponectin Receptor Agonist, Reveals the Ability of Zika Virus to Deregulate Adiponectin Receptor Expression

“…This can be driven by adiponectin or its pharmacological analog AdipoRon with benefits at different levels. Like in a recent study on new therapeutic opportunities to fight West Nile Virus [86], our study demonstrates the value of antiviral molecules targeting the potentiation of responses and metabolic orientation of the host cells rather than targeting the virus particle or viral factors involved in the viral cycle.…”

“…It therefore appears that viruses have strategies to favor the glycolytic use of glucose instead of OXPHOS, to increase viral production and limit antiviral response. In this regard, ZIKV and a few other flaviviruses are known examples of viruses that promote metabolic reprogramming to their benefit [ 82 , 83 , 84 , 85 , 86 ]. Indeed, the AMPK system is a sensor of cellular energy status that responds primarily to changes in the AMP:ATP ratio and activated OXPHOS.…”

NK cell profiling in West Nile virus encephalitis reveals potential metabolic basis for functional inhibition

“…Recently, a proof of concept study demonstrated the druggability of the glycolytic pathway during WNV infection, with pharmacological inhibitors of glycolysis reducing neuroinflammation in a mouse model of WNV infection. 55 While this may be protective to prevent pathogenic immune responses coordinated by specific cell subsets such as brain-infiltrating macrophages which promote CNS damage, this can also inhibit protective virus clearance functions by NK cells. Cell-specific metabolic inhibitors are thus required to target pathogenic cells fueled by glycolysis.…”

Polarised human alveolar epithelia enable identification of dichloroacetate as an effective drug against respiratory viruses

“…Thus, hexokinase inhibitors such as 2-deoxyglucose (2DOG) or 3-bromopyruvate, as well as the lactate dehydrogenase inhibitor oxamate, have been scrutinized as potential antiviral agents, and notably, 2DOG underwent phase II trials on COVID-19 patients [ 49 ]. DCA has been shown to be effective against hepatitis viruses in established tumour cell lines [ 50,51 ], West Nile virus infections in the brain of mice [ 52 ] or SARS-CoV-2 in isolated human kidney cells [ 53 ]. Therefore, the data available reinforces the role of glycolysis, and particularly PDKs, in the viral-induced hijacking of cellular metabolism, pointing to DCA as a broad-spectrum antiviral.…”