TY - JOUR
T1 - Plitidepsin as an Immunomodulator against Respiratory Viral Infections
AU - Losada, Alejandro
AU - Izquierdo-Useros, Nuria
AU - Aviles, Pablo
AU - Vergara-Alert, Júlia
AU - Latino, Irene
AU - Segalés, Joaquim
AU - Gonzalez, Santiago F.
AU - Cuevas, Carmen
AU - Raïch-Regué, Dàlia
AU - Muñoz-Alonso, María J.
AU - Perez-Zsolt, Daniel
AU - Muñoz-Basagoiti, Jordana
AU - Rodon, Jordi
AU - Chang, Lauren A.
AU - Warang, Prajakta
AU - Singh, Gagandeep
AU - Brustolin, Marco
AU - Cantero, Guillermo
AU - Roca, Núria
AU - Pérez, Mònica
AU - Bustos-Morán, Eugenio
AU - White, Kris
AU - Schotsaert, Michael
AU - García-Sastre, Adolfo
N1 - Publisher Copyright:
Copyright © 2024 by The American Association of Immunologists, Inc.
PY - 2024/4/15
Y1 - 2024/4/15
N2 - Plitidepsin is a host-targeted compound known for inducing a strong anti-SARS-CoV-2 activity, as well as for having the capacity of reducing lung inflammation. Because IL-6 is one of the main cytokines involved in acute respiratory distress syndrome, the effect of plitidepsin in IL-6 secretion in different in vitro and in vivo experimental models was studied. A strong plitidepsin-mediated reduction of IL-6 was found in human monocyte-derived macrophages exposed to nonproductive SARS-CoV-2. In resiquimod (a ligand of TLR7/8)-stimulated THP1 human monocytes, plitidepsin-mediated reductions of IL-6 mRNA and IL-6 levels were also noticed. Additionally, although resiquimod-induced binding to DNA of NF-kB family members was unaffected by plitidepsin, a decrease in the regulated transcription by NF-kB (a key transcription factor involved in the inflammatory cascade) was observed. Furthermore, the phosphorylation of p65 that is required for full transcriptional NF-kB activity was significantly reduced by plitidepsin. Moreover, decreases of IL-6 levels and other proinflammatory cytokines were also seen in either SARS-CoV-2 or H1N1 influenza virus-infected mice, which were treated at low enough plitidepsin doses to not induce antiviral effects. In summary, plitidepsin is a promising therapeutic agent for the treatment of viral infections, not only because of its host-targeted antiviral effect, but also for its immunomodulatory effect, both of which were evidenced in vitro and in vivo by the decrease of proinflammatory cytokines.
AB - Plitidepsin is a host-targeted compound known for inducing a strong anti-SARS-CoV-2 activity, as well as for having the capacity of reducing lung inflammation. Because IL-6 is one of the main cytokines involved in acute respiratory distress syndrome, the effect of plitidepsin in IL-6 secretion in different in vitro and in vivo experimental models was studied. A strong plitidepsin-mediated reduction of IL-6 was found in human monocyte-derived macrophages exposed to nonproductive SARS-CoV-2. In resiquimod (a ligand of TLR7/8)-stimulated THP1 human monocytes, plitidepsin-mediated reductions of IL-6 mRNA and IL-6 levels were also noticed. Additionally, although resiquimod-induced binding to DNA of NF-kB family members was unaffected by plitidepsin, a decrease in the regulated transcription by NF-kB (a key transcription factor involved in the inflammatory cascade) was observed. Furthermore, the phosphorylation of p65 that is required for full transcriptional NF-kB activity was significantly reduced by plitidepsin. Moreover, decreases of IL-6 levels and other proinflammatory cytokines were also seen in either SARS-CoV-2 or H1N1 influenza virus-infected mice, which were treated at low enough plitidepsin doses to not induce antiviral effects. In summary, plitidepsin is a promising therapeutic agent for the treatment of viral infections, not only because of its host-targeted antiviral effect, but also for its immunomodulatory effect, both of which were evidenced in vitro and in vivo by the decrease of proinflammatory cytokines.
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U2 - 10.4049/jimmunol.2300426
DO - 10.4049/jimmunol.2300426
M3 - Article
C2 - 38416036
AN - SCOPUS:85189752865
SN - 0022-1767
VL - 212
SP - 1307
EP - 1318
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -