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

作者：Aileen Faist, Sebastian Schloer, Angeles Mecate‐Zambrano, Josua Janowski, André Schreiber, Yvonne Boergeling, Beate Claudine Gisela Conrad, Sriram Kumar, Leonie Toebben, Klaus Schughart, Morris Baumgardt, Mirjana Kessler, Katja Hoenzke, Andreas C. 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 · 发表于：Antiviral Research · 年份：2022 · DOI：10.1016/j.antiviral.2022.105475 · 被引用次数：39 · 研究领域：SARS-CoV-2 and COVID-19 Research、COVID-19 Clinical Research Studies、interferon and immune responses

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.