Zika virus (ZIKV) remains a significant global public health threat due to its association with severe neurological and ocular abnormalities, including microcephaly and congenital glaucoma in infants. Viruses often exploit host metabolic programs, such as energy and lipid metabolism, to support their replication. However, how ZIKV-driven metabolic reprogramming affects the anterior segment of the eye, especially trabecular meshwork (TM) cells, remains poorly defined. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) signaling, fatty acid (FA) metabolism, and lipid droplet (LD) biogenesis in ZIKV-induced ocular pathogenesis using primary human TM cells and an IFNAR1-deficient mouse model. ZIKV infection triggered time-dependent activation of the LKB1-AMPK-ACC signaling axis and significantly increased LD accumulation. Pharmacological activation of AMPK suppressed viral replication, whereas its inhibition enhanced infection, highlighting an antiviral role for AMPK signaling. In contrast, ZIKV promoted LD biogenesis, and inhibition of DGAT1 reduced both LD formation and viral replication, indicating a proviral role for LDs. Modulation of FA metabolism further revealed differential effects on ZIKV infection: saturated FA (palmitate) enhanced viral replication, whereas inhibition of FA oxidation with etomoxir reduced infection. Conversely, unsaturated FAs (oleate and linoleate) suppressed viral replication, in part by impairing viral binding and entry. Collectively, these findings show that ZIKV reshapes host metabolic pathways in TM by differentially engaging AMPK signaling, FA metabolism, and LD biogenesis to promote viral replication and spread in ocular tissue. Targeting these metabolic pathways may offer promising therapeutic avenues for preventing and/or treating ZIKV-associated ocular complications.
Kumar et al. (Thu,) studied this question.