The actively growing field of immunometabolism has taught us how metabolic cellular reactions not only provide a means to generate energy for the cells, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. However, investigating the direct impact of drugs mimicking endogenous metabolites on viruses has never before been attempted. Our recent work uncovered that two Kreb’s cycle-derived endogenous metabolites, the 4-octyl-itaconate (4-OI) and the FDA-approved dimethyl fumarate (DMF) induce a cellular antiviral program, which potently inhibits replication of SARS-CoV2 across different cell lines and primary cell models. This antiviral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a unique type I interferon (IFN)-independent fashion. Further, 4-OI and DMF limited the release of pro-inflammatory cytokines in response to SARS-CoV2 infection and to virus-derived ligands through a mechanism that impaired antiviral immunity. Overall, we demonstrated that 4-OI and DMF drove a distinct and inflammatory silent IFN-independent broad-spectrum antiviral program. The puzzling observation that 4-OI had a strong antiviral effect on some viruses despite its strong capacity to suppress type I IFN prompted us to evaluate the effect of 4-OI as an adjuvant on different interferon sensitive-oncolytic viruses. Indeed, the identification of strategies that significantly potentiate viral replication of clinically relevant and safe viruses, specifically within tumour tissues, could substantially improve oncolysis and stimulate stronger anti-tumour immune responses. Pre-treatment of 4T1 aggressive murine breast cancer cells and 786-O human renal carcinoma cells with 4-OI markedly reduced the replicative properties of HSV-1 g34.5 and Vaccinia Virus JX-594 but dramatically enhanced VSVDM51 infectivity and oncolytic activity <i>in vitro</i>. Altogether, our data suggest that endogenous metabolites are plausible broad-spectrum anti-viral agents that could be used in the treatment of existing or newly emerging viral infections but at the same time can also serve the purpose of virus boosters in oncolytic virotherapy treatment of cancer.

Repurposing of Kreb’s cycle-derived metabolites as antiviral agents and oncolytic virus sensitizers

ACS Fall 2021

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