Human pneumovirus induces IFN-dependent expression of the immune-responsive gene 1 and is inhibited by 4-octyl itaconate in human macrophages

The immunometabolite itaconate, generated by immune-responsive gene 1 (IRG1/ACOD1), and its derivative 4-octyl itaconate (4OI) have been found to modulate inflammation and progression of viral infections, but their effects on the significant respiratory pathogen human metapneumovirus (HMPV) is unknown. Here, we demonstrate that HMPV induces IRG1 expression via a TANK-binding kinase 1, NF-κB-, and interferon (IFN)-dependent manner in human primary macrophages. We further show that the addition of a cell-permeable derivative of itaconate, 4OI, but not itaconate itself or its natural isomer citraconate, reduces HMPV and IFN-β levels in human macrophages. 4OI additionally activated Nrf2, while Nrf2 depletion enhanced HMPV levels, suggesting that Nrf2 mediates the antiviral effect of 4OI on HMPV. Also, we found that 4OI reduced expression of ATP-dependent citrate lyase, a lipid metabolic enzyme that supports HMPV replication. Our study suggests 4OI as a potential compound for targeting HMPV-IFN-β-driven disease and highlights Nrf2-dependent lipid reprogramming as a potential modulator of 4OI antiviral effects.