2-Deoxy-D-glucose attenuates lipopolysaccharide-induced inflammation and restricts Zika, Chikungunya, and Mayaro virus replication in monocyte-derived macrophages.

Re-emerging arthropod-borne viruses such as Mayaro (MAYV), Chikungunya (CHIKV), and Zika (ZIKV) pose a growing global health concern as Aedes mosquito populations expand. These arboviruses infect innate immune cells, particularly monocyte-derived macrophages (MDMs), which support viral replication and serve as reservoirs that facilitate dissemination. Because no effective antiviral treatments are available, strategies that modulate macrophage responses and restrict viral replication are urgently needed. Here, we evaluated the immunomodulatory and antiviral effects of 2-deoxy-D-glucose (2-DG) in human MDMs. First, we assessed how 2-DG shapes transcriptional responses to lipopolysaccharide (LPS), a canonical TLR4 agonist. Co-treatment with 2-DG and LPS induced genes linked to inflammatory, antiviral, and endoplasmic reticulum (ER) stress pathways. Notably, IL10 mRNA and IL-10 protein displayed an inverse relationship with metabolic stress yet correlated positively with inflammatory and antiviral gene expression, whereas GADD34 was positively associated with both inflammatory and ER stress responses, suggesting an integrative regulatory role. We next investigated whether 2-DG pretreatment limits replication of MAYV, CHIKV, and ZIKV in infected MDMs. Antiviral assays demonstrated that 2-DG reduced replication of all three arboviruses by approximately one log10. Additional analyses revealed distinct temporal sensitivities: MAYV and CHIKV showed early and late susceptibility, whereas ZIKV exhibited a distinct kinetic profile. Mechanistic experiments confirmed that 2-DG acts post-entry primarily and reverses the antiviral phenotype observed in LPS-primed MDMs. Collectively, these findings reveal crosstalk among inflammatory, antiviral, and ER stress pathways and demonstrate that 2-DG modulates LPS-driven inflammation while reducing replication of pathogenic arboviruses in human MDMs.