Robust expression of vault RNAs induced by influenza A virus plays a critical role in suppression of PKR-mediated innate immunity.
Bottom Line: Importantly, silencing vtRNA in A549 cells significantly inhibited IAV replication, whereas overexpression of vtRNAs markedly promoted the viral replication.The vtRNA knockdown animals exhibited significantly enhanced resistance to IAV infection, as evidenced by attenuated acute lung injury and spleen atrophy and consequently increased survival rates.In addition, increased expression of vtRNAs was required for efficient suppression of PKR by NS1 during IAV infection.
Affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.Show MeSH
Related in: MedlinePlus
Mentions: It is reported that respirable ASOs represent a novel therapeutic approach for the treatment of lung diseases (46,47). To further define the functional relevance of vtRNA to IAV infection in vivo, C57BL/6 mice were treated with aerosolized ASOs targeting mvtRNA (ASO-mvtRNA) or GFP (ASO-GFP) for 24 h, and then infected with WSN for 96 h. As shown in Figure 4A and B, ASO-mvtRNA significantly downregulated mvtRNA expression in lungs of the mice, as compared with the ASO-GFP control. The mvtRNA knockdown mice displayed slower body weight loss and higher survival rate than the control group during viral infection (Figure 4C and D). All control mice died within 96 h p.i., whereas ∼33% of mvtRNA knockdown mice remained alive within 120 h p.i.. Consistent with these observations, the plaque assay indicated that the viral titers in lung tissues of mvtRNA knockdown mice were significantly lower than that in the control group (Figure 4E), suggesting that silencing mvtRNA inhibits the IAV replication in vivo. In addition, mvtRNA knockdown mice exhibited less-severe organ damage caused by IAV infection, while the control group showed a greater degree of acute lung injury and spleen atrophy (Figure 4F). Consistently, pathologic examination by hematoxylin and eosin (HE) staining displayed less severe edema and reduced infiltration of inflammatory cells across the interalveolar septum in the lungs of infected mice treated with ASOs targeting mvtRNA (Figure 4G). These results indicate that disruption of mvtRNA expression in mice decreases the susceptibility of the animals to IAV infection.
Affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.