Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier

Aileen Faist; Sebastian Schloer; Angeles Mecate-Zambrano; Josua Janowski; André Schreiber; Yvonne Boergeling; Beate C G Conrad; Sriram Kumar; Leonie Toebben; Klaus Schughart; Morris Baumgardt; Mirjana Kessler; Katja Hoenzke; Andreas Hocke; Marcel Trautmann; Wolfgang Hartmann; Hiroki Kato; Ursula Rescher; Anmari Christersson; Joachim Kuehn; Alexander Mellmann; Thorsten Wolff; Philip Kuempers; Alexandros Rovas; Rainer Wiewrodt; Karsten Wiebe; Peter Barth; Stephan Ludwig; Linda Brunotte

doi:10.1016/j.antiviral.2022.105475

Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier

Antiviral Res. 2023 Jan:209:105475. doi: 10.1016/j.antiviral.2022.105475. Epub 2022 Nov 21.

Authors

Aileen Faist¹, Sebastian Schloer², Angeles Mecate-Zambrano³, Josua Janowski⁴, André Schreiber⁴, Yvonne Boergeling³, Beate C G Conrad⁴, Sriram Kumar⁵, Leonie Toebben⁴, Klaus Schughart⁶, Morris Baumgardt⁷, Mirjana Kessler⁸, Katja Hoenzke⁷, Andreas Hocke⁷, Marcel Trautmann⁹, Wolfgang Hartmann⁹, Hiroki Kato¹⁰, Ursula Rescher¹¹, Anmari Christersson⁴, Joachim Kuehn⁴, Alexander Mellmann¹², Thorsten Wolff¹³, Philip Kuempers¹⁴, Alexandros Rovas¹⁴, Rainer Wiewrodt¹⁵, Karsten Wiebe¹⁶, Peter Barth¹⁷, Stephan Ludwig¹⁸, Linda Brunotte¹⁹

Affiliations

¹ Institute of Virology (IVM), University Hospital Muenster, University of Muenster, Muenster, Germany; CiM-IMPRS, University of Muenster, Cells in Motion-International Max Planck Research School - Molecular Biomedicine, Muenster, Germany.
² Research Group "Regulatory Mechanisms of Inflammation", Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, Germany; "Cells in Motion" Interfaculty Center, University of Muenster, Muenster, Germany; Leibniz Institute for Experimental Virology, Hamburg, Germany.
³ Institute of Virology (IVM), University Hospital Muenster, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research, Medical Faculty, University of Muenster, Muenster, Germany.
⁴ Institute of Virology (IVM), University Hospital Muenster, University of Muenster, Muenster, Germany.
⁵ Institute of Virology (IVM), University Hospital Muenster, University of Muenster, Muenster, Germany; EvoPAD Research Training Group 2220, University of Muenster, Muenster, Germany.
⁶ Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany; University of Veterinary Medicine Hannover, Hannover, Germany; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
⁷ Department for Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of the Freie Universität Berlin, Humboldt-University Berlin and Berlin Institute of Health, Berlin, Germany.
⁸ Department for Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of the Freie Universität Berlin, Humboldt-University Berlin and Berlin Institute of Health, Berlin, Germany; Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany.
⁹ Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, Muenster, Germany; Gerhard-Domagk-Institute of Pathology, University of Muenster, Muenster, Germany.
¹⁰ Institute of Cardiovascular Immunology, University Hospital Bonn, University of Bonn, Bonn, Germany.
¹¹ Research Group "Regulatory Mechanisms of Inflammation", Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, Germany; "Cells in Motion" Interfaculty Center, University of Muenster, Muenster, Germany.
¹² Institute of Hygiene, University of Muenster, Muenster, Germany.
¹³ Unit 17 "Influenza and Other Respiratory Viruses", Robert-Koch-Institute, Berlin, Germany.
¹⁴ Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Muenster, Muenster, Germany.
¹⁵ Department of Medicine A, University Hospital Muenster, Muenster, Germany; Department of Respiratory Medicine and Thoracic Oncology, Foundation Mathias Spital, Rheine and Ibbenbueren, Germany.
¹⁶ Department of Thoracic Surgery, University Hospital Muenster, Muenster, Germany.
¹⁷ Gerhard-Domagk-Institute of Pathology, University of Muenster, Muenster, Germany.
¹⁸ Institute of Virology (IVM), University Hospital Muenster, University of Muenster, Muenster, Germany; "Cells in Motion" Interfaculty Center, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research, Medical Faculty, University of Muenster, Muenster, Germany; EvoPAD Research Training Group 2220, University of Muenster, Muenster, Germany.
¹⁹ Institute of Virology (IVM), University Hospital Muenster, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research, Medical Faculty, University of Muenster, Muenster, Germany. Electronic address: brunotte@uni-muenster.de.

Abstract

SARS-CoV-2 is the causative agent of the immune response-driven disease COVID-19 for which new antiviral and anti-inflammatory treatments are urgently needed to reduce recovery time, risk of death and long COVID development. Here, we demonstrate that the immunoregulatory kinase p38 MAPK is activated during viral entry, mediated by the viral spike protein, and drives the harmful virus-induced inflammatory responses. Using primary human lung explants and lung epithelial organoids, we demonstrate that targeting p38 signal transduction with the selective and clinically pre-evaluated inhibitors PH-797804 and VX-702 markedly reduced the expression of the pro-inflammatory cytokines IL6, CXCL8, CXCL10 and TNF-α during infection, while viral replication and the interferon-mediated antiviral response of the lung epithelial barrier were largely maintained. Furthermore, our results reveal a high level of drug synergism of both p38 inhibitors in co-treatments with the nucleoside analogs Remdesivir and Molnupiravir to suppress viral replication of the SARS-CoV-2 variants of concern, revealing an exciting and novel mode of synergistic action of p38 inhibition. These results open new avenues for the improvement of the current treatment strategies for COVID-19.

Keywords: Antiviral response; Immunomodulation; Molnupiravir; Remdesivir; SARS-CoV-2; p38 MAPK.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents* / pharmacology
Antiviral Agents* / therapeutic use
COVID-19* / complications
Humans
Inflammation* / drug therapy
Inflammation* / virology
Lung
Post-Acute COVID-19 Syndrome*
SARS-CoV-2*
Signal Transduction
p38 Mitogen-Activated Protein Kinases*

Substances

Antiviral Agents
p38 Mitogen-Activated Protein Kinases

Supplementary concepts

SARS-CoV-2 variants

Grants and funding

U19 AI100625/AI/NIAID NIH HHS/United States