Abstract
Grail is a well-characterized mediator of metabolic disease, tumour progression, and immune response. However, its role in influenza A virus (IAV) infection remains poorly understood. In this study, we demonstrated that Grail knockdown potentiates IAV infection, whereas Grail overexpression blocks IAV replication. The intranasal administration of IAV to Grail KO mice led to a lower survival rate than in similarly infected wild-type mice. Additionally, IAV-infected Grail KO mice had higher viral titres, greater immune cell infiltration, and increased expression of inflammatory cytokines in the lungs. Mechanistically, we showed that Grail interacts with viral nucleoprotein (NP), targeting it for degradation and inhibiting IAV replication. NP expression was increased in Grail knockdown cells and reduced in cells overexpressing Grail. Collectively, our results demonstrate that Grail acts as a negative regulator of IAV infection and replication by degrading viral NP. These data increase our understanding of the host antiviral response to infection with IAV.
Highlights
Influenza A virus (IAV) is a highly feared pathogen that poses a significant threat to public health and holds the potential for worldwide outbreaks
Gene related to anergy in lymphocytes (Grail) expression is upregulated after influenza A virus (IAV) infection in vitro and in vivo
Mouse data showed that Grail expression was significantly higher in the lung tissue of animals infected with 1000 PFU of WSN/33 H1N1 (WSN) than in control animals (Fig. 1C)
Summary
Influenza A virus (IAV) is a highly feared pathogen that poses a significant threat to public health and holds the potential for worldwide outbreaks (pandemics). Recent genome-wide RNAi screens and supporting experimental evidence have suggested that cellular host proteins interact with IAV at every stage of the viral life cycle[3–6]. The E3 ligase Ccr4-Not transcription complex subunit 4 (CNOT4) is another key host-derived mediator of NP ubiquitination that positively regulates viral RNA replication and does not lead to proteasomal degradation of NP22. Recent work indicates that Grail can regulate host innate immune responses to vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) infections[29]. Despite this body of research, the involvement of Grail during IAV infection and replication has not yet been well characterized. We suggest that Grail is a potential drug target for the further prevention and treatment of IAV infections
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