SRP311775 PRJNA716528 GSE169399 The lysine demethylase LSD1 controls the balance between inflammatory and antiviral responses against coronaviruses Innate responses to coronavirus are highly cell-specific and remain to date incompletely understood. Tissue-resident macrophages, which are infected by SARS-CoV2 in patients but inconsistently in vitro, exert critical but conflicting effects by secreting both anti-viral type I Interferons and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for Covid19, indiscriminately suppress both responses, possibly impairing viral clearance. Here we set up in vitro culture systems with the prototypical murine coronavirus MHV that allow to separately investigate cell-intrinsic and -extrinsic proinflammatory and antiviral activities. We then studied the role of the lysine-demethylase LSD1, previously implicated in innate responses in cancer. We show that the NF-?B-dependent inflammatory response is selectively inhibited by ablating LSD1 with negligible impact on antiviral interferon response. LSD1 ablation additionally unleashed an interferon-independent antiviral response and blocked viral egress through the lysosomal pathway. A cell-intrinsic antiviral and anti-inflammatory activity of LSD1 inhibition was confirmed on in vitro and a recently developed aerosolized in vivo model of human SARS-COV2 infection. These results show that LSD1 controls innate responses against coronaviruses at multiple levels and provide a mechanistic rationale for repurposing LSD1 inhibitors, a class of drugs extensively studied in oncology, for Covid-19 treatment. Overall design: Transcriptional evaluation of the impact of DDP in bone marrow-derived macrophages infected with Murine hepatitis virus strain A59 and on aerosolized mice infected with SARS-COV2 infection. Comparative gene expression profiling analysis of RNA-seq data for lung cells derived from Sars-CoV2 delta variant infected mice. GSE169399