Inhibition of MEK signaling prevents SARS-CoV2-induced lung damage and improves the survival of infected mice

Xie, JingwuKlemsz, Michael J.Kacena, Melissa A.Sandusky, GeorgeZhang, XiaoliKaplan, Mark H.2024-05-092024-05-092022-08-28Xie, J., Klemsz, M. J., Kacena, M. A., Sandusky, G., Zhang, X., & Kaplan, M. H. (2022). Inhibition of MEK signaling prevents SARS-CoV2-induced lung damage and improves the survival of infected mice. Journal of Medical Virology, 94(12), 6097–6102. https://doi.org/10.1002/jmv.28094https://hdl.handle.net/1805/40621Coronavirus disease 2019 (COVID-19) is the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over 500 million confirmed cases of COVID-19 have been recorded, with 6 million deaths. Thus, reducing the COVID-19-related medical burden is an unmet need. Despite a vaccine that is successful in preventing COVID-19-caused death, effective medication to relieve COVID-19-associated symptoms and alleviate disease progression is still in high demand. In particular, one in three COVID-19 patients have signs of long COVID syndrome and are termed long haulers. At present, there are no effective ways to treat long haulers. In this study, we determine the effectiveness of inhibiting mitogen-activated protein kinase (MEK) signaling in preventing SARS-CoV-2-induced lung damage in mice. We showed that phosphorylation of extracellular signal-regulated kinase (ERK), a marker for MEK activation, is high in SARS-CoV-2-infected lung tissues of mice and humans. We show that selumetinib, a specific inhibitor of the upstream MEK kinases, reduces cell proliferation, reduces lung damage following SARS-CoV-2 infection, and prolongs the survival of the infected mice. Selumetinib has been approved by the US Food and Drug Administration (FDA) to treat cancer. Further analysis indicates that amphiregulin (AREG), an essential upstream molecule, was upregulated following SARS-CoV-2 infection. Our data suggest that MEK signaling activation represents a target for therapeutic intervention strategies against SARS-CoV-2-induced lung damage and that selumetinib may be repurposed to treat COVID-19.en-USPublisher PolicyCOVID-19SARS-CoV-2MEKERK phosphorylationKi67lungmouse modelInhibition of MEK signaling prevents SARS-CoV2-induced lung damage and improves the survival of infected miceArticle