Caspase-9 deficiency enhances type I interferon production and confers resistance to viral infection (105.1)

Abstract

Abstract Type I interferons (IFN) are antiviral cytokines that constitute the first line of defense against infection. Recent progress identified the intracellular sensors that recognize viral nucleic acids as well as the downstream signaling pathways leading to type I IFN production. As the unchecked production of type I IFN can be deleterious for the host, these pathways are under tight control by several negative regulatory mechanisms. Here, we identify caspase-9 as a novel negative regulator of type I IFN production, independently of its well described function in the induction of apoptosis. Caspase-9 deficiency leads to the constitutive production of type I IFNs, the activation of the IFN response and to increased resistance to viral infections. Interestingly, this effect is independent of IRF3 and IRF7, two major transcription factors required for IFN expression. The regulation of IFN production by caspase-9 requires its enzymatic activity as well as the presence of Apaf-1 and the downstream effector caspases. Furthermore, we show that genetic inactivation or pharmacological inhibition of caspases activates the IFN response in vivo and confers increased resistance in models of viral infections in vivo. Thus, caspase inhibition represents a new therapeutic approach to activate the IFN response, with potential applications for the treatment and prevention of viral infections responsible for human diseases.