Acute and short-term administrations of delta-9-tetrahydrocannabinol modulate major gut metabolomic regulatory pathways in C57BL/6 mice

AbstractDelta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound in Cannabis, which is studied extensively for its medicinal value. A central gap in the science is the underlying mechanisms surrounding THC’s therapeutic effects and the role of gut metabolite profiles. Using a mass-spectrometry based metabolomics, we show here that intraperitoneal injection of THC in C57BL/6 mice modulates metabolic profiles that have previously been identified as integral to health. Specifically, we investigated the effects of acute (single THC injection denoted here as ‘1X’) and short -term (five THC injections on alternate days denoted as ‘5X’) THC administration on fecal and intestinal tissue metabolite profiles. Results are consistent with the hypothesis that THC administration alters host metabolism by targeting two prominent lipid metabolism pathways: glycerophospholipid metabolism and fatty acid biosynthesis.</jats:p

Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity

The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs(+/−)) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection