SARS-CoV-2-Mediated Lung Edema and Replication Are Diminished by Cystic Fibrosis Transmembrane Conductance Regulator Modulators
José M. Honrubia, Francisco J. Gutierrez-Alvarez, Alejandro Sanz‐Bravo, Ezequiel González-Miranda, Diego Muñoz‐Santos, Carlos Castaño-Rodríguez, Li Wang, Marta Villarejo-Torres, Jorge Ripoll-Gómez, Ana Esteban, Raúl Fernández‐Delgado, Pedro J. Sánchez‐Cordón, Juan Carlos Oliveros, Stanley Perlman, Paul B. McCray, Isabel Sola, Luis Enjuanes
Abstract
Three highly pathogenic human CoVs have been identified: SARS-CoV, MERS-CoV, and SARS-CoV-2. The E protein PBMs of these three CoVs were virulence factors. Gene expression patterns associated with the different PBM motifs in the lungs of infected mice were analyzed by deep sequencing. E protein PBM motif of SARS-CoV and SARS-CoV-2 dysregulated the expression of genes related to ion transport and cell homeostasis. A decrease in the mRNA expression of the cystic fibrosis transmembrane conductance regulator (CFTR), which is essential for edema resolution, was observed. The reduction of CFTR mRNA levels was associated with edema accumulation in the lungs of mice infected with SARS-CoV-2. Compounds that increased the expression and activity of CFTR drastically reduced the production of SARS-CoV-2 and protected against its infection in a mice model. These results allowed the identification of cellular targets for the selection of antivirals.