Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity
Luca Mazzarella; Fabio Santoro; Roberto Ravasio; Paul Massa; Simona Rodighiero; Elena Gaviln; Mauro Romanenghi; Bruno Duso; Emanuele Bonetti; Rani Pallavi; Deborah Trastulli; Isabella Pallavicini; Claudia Gentile; Tommaso Leonardi; Gabriele Buttinelli; Sebastiano Pasqualato; Angela Di Martino; Giorgio Fedele; Ilaria Schiavoni; Paola Stefanelli; Giuseppe Meroni; Christian Steinkuhler; Gianluca Fossati; Saverio Minucci; Pier Giuseppe Pelicci.
Preprint
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| PREPRINT-BIORXIV | ID: ppbiorxiv-441948
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 SummaryTargeting a chromatin-modifying enzyme in coronavirus infections curbs tissue-damage without affecting antiviral response
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