Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice

Anna Macht; Yiqi Huang; Line S. Reinert; Vincent Grass; Kristin Lohmer; Elke Tatjana Aristizabal Prada; Eveline Babel; Alexandra Semmler; Wen Zhang; Andrea Wegner; Eva Lichtenegger-Hartl; Sonja Haas; Günther Hasenpusch; Steffen Meyer; Søren R. Paludan; Andreas Pichlmair; Carsten Rudolph; Thomas Langenickel

doi:10.1038/s44319-024-00216-4

Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice

Anna Macht, Yiqi Huang, Line S. Reinert, Vincent Grass, Kristin Lohmer, Elke Tatjana Aristizabal Prada, Eveline Babel, Alexandra Semmler, Wen Zhang, Andrea Wegner, Eva Lichtenegger-Hartl, Sonja Haas, Günther Hasenpusch, Steffen Meyer, Søren R. Paludan, Andreas Pichlmair, Carsten Rudolph, Thomas Langenickel

Medicine and Health

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	3777-3788
Number of pages	12
Journal	EMBO Reports
Volume	25
Issue number	9
DOIs	https://doi.org/10.1038/s44319-024-00216-4
State	Published - 10 Sep 2024

Keywords

Immunology
Infectious Diseases
Interferon
Nucleic-acid Therapeutics
Viral Infection

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s44319-024-00216-4

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Macht, A., Huang, Y., Reinert, L. S., Grass, V., Lohmer, K., Aristizabal Prada, E. T., Babel, E., Semmler, A., Zhang, W., Wegner, A., Lichtenegger-Hartl, E., Haas, S., Hasenpusch, G., Meyer, S., Paludan, S. R., Pichlmair, A., Rudolph, C., & Langenickel, T. (2024). Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice. EMBO Reports, 25(9), 3777-3788. https://doi.org/10.1038/s44319-024-00216-4

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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.",

keywords = "Immunology, Infectious Diseases, Interferon, Nucleic-acid Therapeutics, Viral Infection",

author = "Anna Macht and Yiqi Huang and Reinert, {Line S.} and Vincent Grass and Kristin Lohmer and {Aristizabal Prada}, {Elke Tatjana} and Eveline Babel and Alexandra Semmler and Wen Zhang and Andrea Wegner and Eva Lichtenegger-Hartl and Sonja Haas and G{\"u}nther Hasenpusch and Steffen Meyer and Paludan, {S{\o}ren R.} and Andreas Pichlmair and Carsten Rudolph and Thomas Langenickel",

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doi = "10.1038/s44319-024-00216-4",

language = "English",

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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 & Langenickel, T 2024, 'Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice', EMBO Reports, vol. 25, no. 9, pp. 3777-3788. https://doi.org/10.1038/s44319-024-00216-4

TY - JOUR

T1 - Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice

AU - Macht, Anna

AU - Huang, Yiqi

AU - Reinert, Line S.

AU - Grass, Vincent

AU - Lohmer, Kristin

AU - Aristizabal Prada, Elke Tatjana

AU - Babel, Eveline

AU - Semmler, Alexandra

AU - Zhang, Wen

AU - Wegner, Andrea

AU - Lichtenegger-Hartl, Eva

AU - Haas, Sonja

AU - Hasenpusch, Günther

AU - Meyer, Steffen

AU - Paludan, Søren R.

AU - Pichlmair, Andreas

AU - Rudolph, Carsten

AU - Langenickel, Thomas

PY - 2024/9/10

Y1 - 2024/9/10

N2 - 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.

AB - 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.

KW - Immunology

KW - Infectious Diseases

KW - Interferon

KW - Nucleic-acid Therapeutics

KW - Viral Infection

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U2 - 10.1038/s44319-024-00216-4

DO - 10.1038/s44319-024-00216-4

M3 - Article

C2 - 39060455

AN - SCOPUS:85200025824

SN - 1469-221X

VL - 25

SP - 3777

EP - 3788

JO - EMBO Reports

JF - EMBO Reports

IS - 9

ER -

Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice

Abstract

Keywords

UN SDGs

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