DExD/H box RNA helicases, such as the RIG-I-like receptors (RLR), are important components of the innate immune system. Here we demonstrate a pivotal and sex-specific role for the heterosomal isoforms of the DEAD box RNA helicase DDX3 in the immune system. Mice lacking DDX3X during hematopoiesis showed an altered leukocyte composition in bone marrow and spleen and a striking inability to combat infection with Listeria monocytogenes. Alterations in innate immune responses resulted from decreased effector cell availability and function as well as a sex-dependent impairment of cytokine synthesis. Thus, our data provide further in vivo evidence for an essential contribution of a non-RLR DExD/H RNA helicase to innate immunity and suggest it may contribute to sex-related differences in resistance to microbes and resilience to inflammatory disease.

Signal transducer and activator of transcription 1 (STAT1) plays a pivotal role in the innate immune system by directing the transcriptional response to interferons (IFNs). STAT1 is activated by Janus kinase (JAK)-mediated phosphorylation of Y701. To determine whether STAT1 contributes to cellular responses without this phosphorylation event, we generated mice with Y701 mutated to a phenylalanine (Stat1