Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity

Mazzarella, Luca; Santoro, Fabio; Ravasio, Roberto; Massa, Paul E.; Rodighiero, Simona; Gavilán, Elena; Romanenghi, Mauro; Duso, Bruno Achutti; Bonetti, Emanuele; Pallavi, Rani; Trastulli, Deborah; Pallavicini, Isabella; Gentile, Claudia; Leonardi, Tommaso; Pasqualato, Sebastiano; Buttinelli, Gabriele; Martino, Angela Di; Fedele, Giorgio; Schiavoni, Ilaria; Stefanelli, Paola; Meroni, Giuseppe; Steinkuhler, Christian; Fossati, Gianluca; Minucci, Saverio; Pelicci, Pier Giuseppe

Tissue-resident macrophages exert critical but conflicting effects on the progression of coronavirus infections 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, and provide limited clinical benefit. Here we set up a mouse in vitro co-culture system that reproduces the macrophage response to SARS-CoV2 seen in patients and allows quantitation of inflammatory and antiviral activities. We show that the NFKB-dependent inflammatory response can be selectively inhibited by ablating the lysine-demethylase LSD1, which additionally unleashed interferon-independent ISG activation and blocked viral egress through the lysosomal pathway. These results provide a rationale for repurposing LSD1 inhibitors, a class of drugs extensively studied in oncology, for Covid-19 treatment. One-Sentence Summary Targeting a chromatin-modifying enzyme in coronavirus infections curbs tissue-damage without affecting antiviral response