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Contribution of host miRNA-223-3p to SARS-CoV-induced lung inflammatory pathology

ABSTRACT: Severe acute respiratory syndrome coronavirus (SARS-CoV) and the closely related SARS-CoV-2 are emergent highly pathogenic human respiratory viruses causing acute lethal disease associated with lung damage and dysregulated inflammatory responses. SARS-CoV envelope protein (E) is a virulence factor involved in the activation of various inflammatory pathways. Here, we study the contribution of host miRNAs to the virulence mediated by E protein. Small RNAseq analysis of infected mouse lungs identified miRNA-223 as a potential regulator of pulmonary inflammation, since it was significantly increased in SARS-CoV-WT virulent infection as compared to the attenuated SARS-CoV-∆E infection. In vivo inhibition of miRNA-223-3p increased mRNA levels of pro-inflammatory cytokines and NLRP3 inflammasome, suggesting that during lung infection, miRNA-223 might contribute to restrict an excessive inflammatory response. Interestingly, miRNA-223-3p inhibition also increased the levels of the CFTR transporter, which is involved in edema resolution and was significantly downregulated in the lungs of mice infected with the virulent SARS-CoV-WT virus. At the histopathological level, a decrease in the pulmonary edema was observed when miR-223-3p was inhibited, suggesting that miRNA-223-3p was involved in the regulation of the SARS-CoV-induced inflammatory pathology. These results indicate that miRNA-223 participates in the regulation of E protein mediated- inflammatory response during SARS-CoV infection by targeting different host mRNAs involved in the pulmonary inflammation and identify miRNA-223 as a potential therapeutic target in SARS-CoV infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE180563 | GEO | 2022/02/04

REPOSITORIES: GEO

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Project description:The three human deadly coronaviruses (CoVs) (SARS-CoV, MERS-CoV and SARS-CoV-2) have infected around eight thousand, two thousand six hundred and 262 million people so far (December 2021), causing the death of 10%, 37% and 2% of them, respectively, so their implication in health is very important. These CoVs have proteins with a PBM motif that binds to PDZ cell domains. PDZ domains are found in more than 400 cellular proteins, therefore, viruses with PBM motifs have a high potential to modify cell behavior. It was studied the implication of the E protein PBM motif of various virulent or attenuated human CoVs (hCoVs) in the pathogenesis induced by these viruses. Variants of SARS-CoV, MERS-CoV and SARS-CoV-2 that lack the E protein PBM have been generated by reverse genetics and their pathogenicity has been analyzed in mice. The PBM motifs of these three hCoVs have been shown to be virulence factors and participate in their replication. Furthermore, a collection of SARS-CoV mutants has been constructed in which the E protein PBM domain was replaced by the one derived from virulent or attenuated hCoVs, and their virulence was analyzed. A virulence gradient was observed, depending on whether the E protein PBM domain was derived from an attenuated or virulent hCoV. The gene expression patterns associated with the different PBM motifs in lungs of mice infected with SARS-CoV was analyzed by deep sequencing of the mRNAs expressed in lungs of infected mice, and it was observed that the E protein PBM motif of SARS-CoV and SARS-CoV-2 dysregulates the expression of genes related to ion transport and cell homeostasis. Specifically, a decrease of 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 lungs of mice infected with SARS-CoV and SARS-CoV-2. The effect of compounds that modulate the expression and activity of CFTR on the pathogenesis and replication of SARS-CoV-2 was studied and it was observed that these compounds drastically reduced the production of SARS-CoV-2 in cell culture and protect against SARS-CoV-2 pathogenesis. These results showed the high relevance of the PBM motif in the replication and virulence of CoVs, and have allowed the identification of cellular targets for the selection of antivirals.

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Contribution of host miRNA-223-3p to SARS-CoV-induced lung inflammatory pathology

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