Type I IFN-induced viperin promotes Mycobacterium tuberculosis survival by suppressing the protective COX-2/PGE2/IL-1β axis in macrophages

Abstract

Type I interferon (IFN) signaling is associated with detrimental outcomes during Mycobacterium tuberculosis (Mtb) infection, in part through antagonism of IL-1β-mediated protective immunity. Viperin, an IFN-stimulated gene induced downstream of type I IFN, has previously been implicated in suppressing innate immune responses during Mtb infection. However, whether Viperin modulates IL-1β-mediated protective pathways that contribute to host control of Mtb remains unclear. Viperin expression was robustly induced following Mtb infection in a type I IFN-dependent manner in bone marrow-derived macrophages and murine lungs. Genetic deletion of Viperin significantly reduced bacterial burden both in vitro and in vivo . Mechanistically, Viperin-deficient ( Viperin −/− ) macrophages exhibited enhanced IL-1β responses accompanied by increased COX-2 expression and elevated PGE 2 production. These changes were associated with improved control of intracellular Mtb. The enhanced antibacterial activity of Viperin −/− macrophages was dependent on COX-2 activity, as treatment with the selective COX-2 inhibitor celecoxib significantly reduced bacterial restriction. Conversely, Viperin overexpression suppressed inflammatory mediator production and impaired macrophage control of Mtb. These findings identify Viperin as a functional downstream effector of type I IFN signaling that restrains IL-1β–associated antibacterial responses during Mtb infection. By linking Viperin to regulation of the IL-1β/COX-2/PGE 2 pathway, our study provides mechanistic insight into how type I IFN signaling can undermine host defense in tuberculosis and supports further exploration of Viperin as a potential target for host-directed therapeutic strategies.