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Sci Signal
. 2023 Dec 19;16(816):eade0326.
doi: 10.1126/scisignal.ade0326. Epub 2023 Dec 19. Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses
Luca Mazzarella 1 , Fabio Santoro 1 , Roberto Ravasio 1 , Valeria Fumagalli 2 3 4 , Paul E Massa 1 , Simona Rodighiero 1 , Elena Gavilán 1 , Mauro Romanenghi 1 , Bruno A Duso 1 , Emanuele Bonetti 1 , Lara Manganaro 5 6 , Rani Pallavi 1 , Deborah Trastulli 1 , Isabella Pallavicini 1 , Claudia Gentile 1 , Silvia Monzani 1 , Tommaso Leonardi 7 , Sebastiano Pasqualato 1 , Gabriele Buttinelli 8 , Angela Di Martino 8 , Giorgio Fedele 8 , Ilaria Schiavoni 8 , Paola Stefanelli 8 , Giuseppe Meroni 9 , Raffaele de Francesco 5 6 , Christian Steinkuhler 10 , Gianluca Fossati 10 , Matteo Iannacone 2 3 4 , Saverio Minucci 1 11 , Pier Giuseppe Pelicci 1 12
Affiliations
Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19), indiscriminately suppress both responses, possibly impairing viral clearance. Here, we established in vitro cell culture systems that enabled us to separately investigate the cell-intrinsic and cell-extrinsic proinflammatory and antiviral activities of mouse macrophages infected with the prototypical murine coronavirus MHV-A59. We showed that the nuclear factor κB-dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway. The macrophage-intrinsic antiviral and anti-inflammatory activity of Lsd1 inhibition was confirmed in vitro and in a humanized mouse model of SARS-CoV-2 infection. These results suggest that LSD1 controls innate immune responses against coronaviruses at multiple levels and provide a mechanistic rationale for potentially repurposing LSD1 inhibitors for COVID-19 treatment.
. 2023 Dec 19;16(816):eade0326.
doi: 10.1126/scisignal.ade0326. Epub 2023 Dec 19. Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses
Luca Mazzarella 1 , Fabio Santoro 1 , Roberto Ravasio 1 , Valeria Fumagalli 2 3 4 , Paul E Massa 1 , Simona Rodighiero 1 , Elena Gavilán 1 , Mauro Romanenghi 1 , Bruno A Duso 1 , Emanuele Bonetti 1 , Lara Manganaro 5 6 , Rani Pallavi 1 , Deborah Trastulli 1 , Isabella Pallavicini 1 , Claudia Gentile 1 , Silvia Monzani 1 , Tommaso Leonardi 7 , Sebastiano Pasqualato 1 , Gabriele Buttinelli 8 , Angela Di Martino 8 , Giorgio Fedele 8 , Ilaria Schiavoni 8 , Paola Stefanelli 8 , Giuseppe Meroni 9 , Raffaele de Francesco 5 6 , Christian Steinkuhler 10 , Gianluca Fossati 10 , Matteo Iannacone 2 3 4 , Saverio Minucci 1 11 , Pier Giuseppe Pelicci 1 12
Affiliations
- PMID: 38113337
- DOI: 10.1126/scisignal.ade0326
Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19), indiscriminately suppress both responses, possibly impairing viral clearance. Here, we established in vitro cell culture systems that enabled us to separately investigate the cell-intrinsic and cell-extrinsic proinflammatory and antiviral activities of mouse macrophages infected with the prototypical murine coronavirus MHV-A59. We showed that the nuclear factor κB-dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway. The macrophage-intrinsic antiviral and anti-inflammatory activity of Lsd1 inhibition was confirmed in vitro and in a humanized mouse model of SARS-CoV-2 infection. These results suggest that LSD1 controls innate immune responses against coronaviruses at multiple levels and provide a mechanistic rationale for potentially repurposing LSD1 inhibitors for COVID-19 treatment.