USP18 inhibits protective immune responses and the intracellular control of Mycobacterium tuberculosis in macrophages.

We compared the transcriptome profile of M. tuberculosis-infected murine bone marrow derived macrophages (BMM) treated with either the USP18 small molecule inhibitor BB7 or an inactive control (NC), and uninfected controls as described below. We identified 710 differentially expressed genes (DEGs) between uninfected and Mtb BMM and 243 DEGs comparing Mtb-BB7 vs Mtb BMM, 129 of these DEGs were upregulated. Gene ontology (GO) analysis showed enrichment of pathways related to antiviral responses, innate immune activation and inflammasome signalling when comparing Mtb-BB7 vs Mtb BMM. Conversely, genes associated with stress responses, hypoxia and antioxidant activity were downregulated in Mtb-BB7. Overall design: RNA seq was performed in triplicate independent cultures of BMM treated either with10 mM uM BB7 or NC , infected 4 h after treatment with M. tuberculosis at a MOI of 5:1. RNA was extracted 8h after Mtb infection from uninfected BMM controls (Control), Mtb infected BMM treated with NC (Mtb), and MGO-treated, Mtb-infected BMM (Mtb-BB7).