The Mechanism Study Of Progranulin Facilitating Influenza A Virus (H1N1)infection

Seasonal flu is a serious threat to humans,especially for the elderly people and children.Even with the developments of influenza virus targeted drugs and the utilization of flu vaccines,the threat of flu is still difficult to control.Progranulin(PGRN)is an important immune regulatory protein and is associated with several viruses and bacterial infections.It is reported that PGRN knock out mice are more resistant to influenza A virus(IAV)infection with lower body weight loss and mortality.But how PGRN functions during IAV infection at the cellular and molecular levels is poorly understood.Here we try to elucidate PGRN's functions during IAV infection with cellular and molecular approaches.By knocking down(KD)PGRN expression in A549 human lung epithelia cell line and by using His-tagged recombinant human PGRN protein,infection of A549 cells with the PR8 strain of IAV shows that PGRN KD results in lower levels of viral mRNA and protein expression and adding back PGRN-His can increase viral protein expression.Utilizing an enzymatic viruslike particle assay for measuring viral entry,we demonstrate that PGRN KD in A549 cells leads to reduced IAV entry and we establsish a basic mathematical model to simulate this process.In summary,we are the first to demonstrate that PGRN deficiency in lung epithelial cells can reduce the virus entry and viral protein expression,thereby potentially protecting target cells from infection associated pathogenesis and mortality.Thus,this study establishes the cellular and molecular basis on which to further explore the activities of PGRN in influenza infection and to develop novel and efficacious therapeutic interventions.