Plitidepsin as an Immunomodulator against Respiratory Viral Infections

Alejandro Losada, Nuria Izquierdo-Useros, Pablo Aviles, Júlia Vergara-Alert, Irene Latino, Joaquim Segalés, Santiago F. Gonzalez, Carmen Cuevas, Dàlia Raïch-Regué, María J. Muñoz-Alonso, Daniel Perez-Zsolt, Jordana Muñoz-Basagoiti, Jordi Rodon, Lauren A. Chang, Prajakta Warang, Gagandeep Singh, Marco Brustolin, Guillermo Cantero, Núria Roca, Mònica PérezEugenio Bustos-Morán, Kris White, Michael Schotsaert, Adolfo García-Sastre

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1307-1318
Number of pages12
JournalJournal of Immunology
Volume212
Issue number8
DOIs
StatePublished - 15 Apr 2024

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