1. Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice.
- Author
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Macht A, Huang Y, Reinert LS, Grass V, Lohmer K, Aristizabal Prada ET, Babel E, Semmler A, Zhang W, Wegner A, Lichtenegger-Hartl E, Haas S, Hasenpusch G, Meyer S, Paludan SR, Pichlmair A, Rudolph C, and Langenickel T
- Subjects
- Animals, Female, Humans, Mice, Antiviral Agents, Chlorocebus aethiops, Immunomodulation, Interferons metabolism, Liposomes, Nanoparticles administration & dosage, Viral Load, Virus Replication, COVID-19 immunology, COVID-19 prevention & control, COVID-19 virology, RNA, Messenger genetics, RNA, Messenger metabolism, SARS-CoV-2 immunology, SARS-CoV-2 genetics, SARS-CoV-2 physiology, Interferon Lambda administration & dosage, Interferon Lambda genetics
- Abstract
RNA vaccines elicit protective immunity against SARS-CoV-2, but the use of mRNA as an antiviral immunotherapeutic is unexplored. Here, we investigate the activity of lipidoid nanoparticle (LNP)-formulated mRNA encoding human IFNλ1 (ETH47), which is a critical driver of innate immunity at mucosal surfaces protecting from viral infections. IFNλ1 mRNA administration promotes dose-dependent protein translation, induction of interferon-stimulated genes without relevant signs of unspecific immune stimulation, and dose-dependent inhibition of SARS-CoV-2 replication in vitro. Pulmonary administration of IFNλ1 mRNA in mice results in a potent reduction of virus load, virus-induced body weight loss and significantly increased survival. These data support the development of inhaled administration of IFNλ1 mRNA as a potential prophylactic option for individuals exposed to SARS-CoV-2 or at risk suffering from COVID-19. Based on the broad antiviral activity of IFNλ1 regardless of virus or variant, this approach might also be utilized for other respiratory viral infections or pandemic preparedness., (© 2024. The Author(s).)
- Published
- 2024
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