The pregnane X receptor is a novel host target for dengue virus infection that reprograms lipid metabolism and suppresses the immune response.

Dengue virus (DENV) is the main mosquito-transmitted virus in the world, with approximately 500,000 people developing severe DENV infection (dengue hemorrhagic fever or dengue shock syndrome) annually. DENV is localized principally to tropical and subtropical regions, but its range is expanding north and south due to climate change and urbanization. Therapeutic options are currently limited, and the identification of new antiviral targets is urgently needed. Here, we demonstrated that, in macrophages, DENV2 increases lipid droplet biogenesis and the expression of genes involved in triglyceride and cholesterol synthesis and accumulation while decreasing the immune response through the activation of the pregnane X receptor (PXR), a nuclear ligand-dependent transcription factor. PXR inhibition with okadaic acid or ketoconazole (KTZ) partially restored interleukin (IL)-1β, IL-6, tumor necrosis factor-α, IL-12, interferon (IFN)-γ, and IFN-α levels and blocked the DENV2 infection-induced expression of Srebp2, Pparγ, Cd36, and Sqle. KTZ, a PXR antagonist and United States Food and Drug Administration-approved antimycotic drug, also reduced viral replication in vitro and in vivo. We additionally determined that the DENV2 capsid protein drives PXR activation. Thus, the present investigation led to the characterization of the PXR-dependent reprogramming of fatty-acid and cholesterol metabolism and immune suppression promoted by DENV2 to facilitate its replication. Taken together, our data position PXR as a new druggable target for dengue treatment.