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

Mazzarella, L.; Santoro, F.; Ravasio, R.; Massa, P.; Rodighiero, S.; Gaviln, E.; Romanenghi, M.; Duso, B.; Bonetti, E.; Pallavi, R.; Trastulli, D.; Pallavicini, I.; Gentile, C.; Leonardi, T.; Buttinelli, G.; Pasqualato, S.; Di Martino, A.; Fedele, G.; Schiavoni, I.; Stefanelli, P.; Meroni, G.; Steinkuhler, C.; Fossati, G.; Minucci, S.; Pelicci, P. G.

doi:10.1101/2021.05.02.441948

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bioRxiv · 10.1101/2021.05.02.441948

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

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Abstract

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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Mazzarella, L., Santoro, F., Ravasio, R., Massa, P., Rodighiero, S., Gaviln, E., Romanenghi, M., Duso, B., Bonetti, E., Pallavi, R., Trastulli, D., Pallavicini, I., Gentile, C., Leonardi, T., Buttinelli, G., Pasqualato, S., Di Martino, A., Fedele, G., Schiavoni, I., Stefanelli, P., Meroni, G., Steinkuhler, C., Fossati, G., Minucci, S., Pelicci, P. G.. 2021-05-03. Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity. https://doi.org/10.1101/2021.05.02.441948

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